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PubMed2006

Nationwide survey of juvenile muscular atrophy of distal upper extremity (Hirayama disease) in Japan.

Juvenile muscular atrophy of the distal upper extremity (JMADUE, Hirayama disease) was first reported in 1959 as 'juvenile muscular atrophy of unilateral upper extremity'. Since then, similar patients in their teens or 20s have been described, under a variety of names, not only in Japan, but also in other Asian countries, as well as Europe and North America. Biomechanical abnormalities associated with JMADUE have recently been reported through various imaging examinations, proposing its disease mechanism. Since JMADUE differs from motor neuron disease, or spinal muscular atrophy, this disease entity should be more widely recognized, and early detection and effective treatments should be considered. We report an epidemiological study in Japan. Two nationwide questionnaire-based surveys, conducted in Japan from 1996 to 1998, identified 333 cases. The numbers of patients per year, distribution of ages at onset, mode of onset, time lapse between onset and quiescence, neurological signs and symptoms, imaging findings, and the effects of conservative treatments were analyzed. The peak age was 15 to 17 years, with a marked male preponderance, usually a slow onset and progression, and quiescence six or fewer years after onset. There was a predominantly unilateral hand and forearm involvement with 'cold paresis'. The imaging findings are described.

Adolescent↗

PubMed2005

Transplanted ALDHhiSSClo neural stem cells generate motor neurons and delay disease progression of nmd mice, an animal model of SMARD1.

Spinal muscular atrophy with respiratory distress type 1 (SMARD1) is an infantile autosomal-recessive motor neuron disease caused by mutations in the immunoglobulin micro-binding protein 2. We investigated the potential of a spinal cord neural stem cell population isolated on the basis of aldehyde dehydrogenase (ALDH) activity to modify disease progression of nmd mice, an animal model of SMARD1. ALDH(hi)SSC(lo) stem cells are self-renewing and multipotent and when intrathecally transplanted in nmd mice generate motor neurons properly localized in the spinal cord ventral horns. Transplanted nmd animals presented delayed disease progression, sparing of motor neurons and ventral root axons and increased lifespan. To further investigate the molecular events responsible for these differences, microarray and real-time reverse transcription-polymerase chain reaction analyses of wild-type, mutated and transplanted nmd spinal cord were undertaken. We demonstrated a down-regulation of genes involved in excitatory amino acid toxicity and oxidative stress handling, as well as an up-regulation of genes related to the chromatin organization in nmd compared with wild-type mice, suggesting that they may play a role in SMARD1 pathogenesis. Spinal cord of nmd-transplanted mice expressed high transcript levels for genes related to neurogenesis such as doublecortin (DCX), LIS1 and drebrin. The presence of DCX-expressing cells in adult nmd spinal cord suggests that both exogenous and endogenous neurogeneses may contribute to the observed nmd phenotype amelioration.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗

PubMed1996

Advances in SMA research: review of gene deletions.

The term spinal muscular atrophy (SMA) is used to encompass a group of inherited disorders in which the striking pathological feature is loss of the cell bodies of alpha motor neurons in the anterior horn cell of the spinal cord and, in some cases, of the bulbar motor nuclei. Although the pathological features of these disorders have been well characterized, the nature of the primary underlying biochemical abnormality remains to be determined. In the 1990s genetic linkage was established for the childhood onset recessive forms of SMA (types I, II and III) to markers mapping to the chromosomal region 5q11.2-13.3. Physical maps of the region were then constructed, several candidate genes isolated and in 1995 deletions in two genes, the survival motor neuron (SMN) gene and the neuronal apoptosis inhibitory protein (NAIP) gene, were identified in significant numbers of patients. Already the impact of the characterization of these deletions is being seen in clinical practice in terms of aiding diagnosis in symptomatic cases and in prenatal diagnosis. As discussed in this review however, several questions remain unresolved. It is unclear whether deletions in one or both of these genes, or indeed in other, as yet unidentified, genes are important in generating the SMA phenotype. The function of the protein product of the SMN gene is unknown. The NAIP gene encodes a protein which inhibits apoptosis in a mammalian cell line: is it disruption of this function which is relevant in SMA? What underlies the variation in disease severity evident both between and within families? Resolution of such issues is of crucial importance if the identification of these deleted gene sequences is to lead to the development of rational therapies for motor neuron diseases.

Chromosome Aberrations↗

PubMed2008

Intravascular AAV9 preferentially targets neonatal neurons and adult astrocytes.

Delivery of genes to the brain and spinal cord across the blood-brain barrier (BBB) has not yet been achieved. Here we show that adeno-associated virus (AAV) 9 injected intravenously bypasses the BBB and efficiently targets cells of the central nervous system (CNS). Injection of AAV9-GFP into neonatal mice through the facial vein results in extensive transduction of dorsal root ganglia and motor neurons throughout the spinal cord and widespread transduction of neurons throughout the brain, including the neocortex, hippocampus and cerebellum. In adult mice, tail vein injection of AAV9-GFP leads to robust transduction of astrocytes throughout the entire CNS, with limited neuronal transduction. This approach may enable the development of gene therapies for a range of neurodegenerative diseases, such as spinal muscular atrophy, through targeting of motor neurons, and amyotrophic lateral sclerosis, through targeting of astrocytes. It may also be useful for rapid postnatal genetic manipulations in basic neuroscience studies.

Animals↗

PubMed1996

Spinal and bulbar muscular atrophy: androgen receptor dysfunction caused by a trinucleotide repeat expansion.

Kennedy's disease (spinal and bulbar muscular atrophy) is an X-linked form of motor neuron disease that affects adult men. The syndrome is characterized by progressive atrophy of the limb muscles, pelvic and shoulder girdles and dysphagia and dysarthria, and is caused by the degeneration of spinal and bulbar motor neurons. Kennedy's disease is caused by a trinucleotide repeat expansion of a CAG repeat in exon A of the androgen receptor gene, and is one of a group of neurological diseases caused by trinucleotide repeat expansions in different genes. The mutation in Kennedy's disease involves an increased number of glutamine residues in the amino-terminal domain of the receptor. Point mutations and deletions in the androgen receptor gene cause androgen insensitivity syndrome, however subjects with Kennedy's disease have normal virilization, although progressive gynaecomastia, testicular atrophy and infertility may occur. Androgen receptors are expressed widely in the normal brain, and in the anterior horn cells of the spinal cord; however, their role in neuronal tissue is not known, nor is it known how the androgen receptor gene mutation causes neuronal degeneration. Kennedy's disease is likely to be a 'gain of function' abnormality, so that the presence of the receptor with an increased number of glutamines is toxic to motor neurons. It is possible that the mutation alters interaction of the receptor with other neuronal transcription factors, or neuronotoxicity may occur because of a non-specific effect caused by the presence of a protein with a large homoglutamine domain. Studies of patients with Kennedy's disease have shown that expression of androgen receptor mRNA and protein in spinal cord may be decreased, as can be the affinity of the mutant receptor for androgen. In vitro studies have shown impaired transcription activation ability of the mutant androgen receptor. The age at onset of Kennedy's disease may correlate with the size of the CAG repeat, however there is a large degree of variability of age at onset between subjects with the same number of repeats. Further study of the effect of the Kennedy's disease mutation on androgen receptor function in motor neurons will allow us to increase our understanding of the pathogenesis of this disease.

Animals↗

PubMed2005

Activation of RNA metabolism-related genes in mouse but not human tissues deficient in SMN.

Mutations of the survival of motor neuron gene (SMN1) are responsible for spinal muscular atrophies (SMA), a frequent recessive autosomal motor neuron disease. SMN is involved in various processes including RNA metabolism. However, the molecular pathway linking marked deficiency of SMN to SMA phenotype remains unclear. Homozygous deletion of murine Smn exon 7 directed to neurons or skeletal muscle causes severe motor axonal or myofiber degeneration, respectively. With the use of cDNA microarrays, expression profiles of 8,400 genes were analyzed in skeletal muscle and spinal cord of muscular and neuronal mutants, respectively, and compared with age-matched controls. A high proportion of genes (20 of 429, 5%) was involved in pre-mRNA splicing, ribosomal RNA processing, or RNA decay, and 18 of them were upregulated in mutant tissues. By analyzing other neuromuscular disorders, we showed that most of them (14 of 18) were specific to the SMN defect. Quantitative PCR analysis of these transcripts showed that gene activation was an early adaptive response to the lack but not reduced amount of full-length SMN in mouse mutant tissues. In human SMA tissues, activation of this program was not observed, which could be ascribed to the reduction but not the absence of full-length SMN.

Animals↗

PubMed1993

Abnormal acidic amino acids and N-acetylaspartylglutamate in hereditary canine motoneuron disease.

Hereditary canine spinal muscular atrophy (HCSMA) is a lower motor neuron disease found in Brittany Spaniels that shares clinical and pathological features with human amyotrophic lateral sclerosis (ALS). Since acidic excitatory amino acids and the neuropeptide N-acetyl-aspartyl-glutamate (NAAG) are reduced in spinal cord and cerebral cortex in ALS, the levels of these substances were measured in nervous tissue in Brittany Spaniels heterozygous and homozygous for HCSMA. Significant reductions in the levels of endogenous aspartate, glutamate, N-acetylaspartate (NAA), and NAAG were found in the spinal cord in homozygous but not heterozygous HCSMA. In contrast, the activity of N-acetylated-alpha-linked-amino dipeptidase (NAALADase), an enzyme that cleaves NAAG into NAA and Glu, was significantly increased. None of these parameters was affected in the motor cortex or occipital cortex. Since NAA and NAAG are highly concentrated in motoneurons, they may play a role in the pathogenesis of motor neuron disease.

Amino Acids↗

PubMed1971

Characteristic clinical findings in some neurogenic myopathies and in some myogenic myopathies causing muscular weakness, hypotonia and atrophy in infancy and early childhood.

Some conditions causing neurogenic or myogenic myopathy are reviewed and illustrated by cases of 1) perinatal cervical cord injury; 2) various types of progressive spinal muscular atrophy and 3) congenital muscular dystrophy, Duchenne-like type of muscular dystrophy, limb-girdle type of muscular dystrophy. All the cases of muscular dystrophy described here occurred in girls.

Adolescent↗

PubMed1999

The drastic reduction of SMN protein in SMA I spinal cord motor neurons is not due to inefficient transcription.

Spinal muscular atrophy (SMA) is caused by homozygous absence of the telomeric copy of the survival motor neuron (SMNt) gene. SMNt and its homologous centromeric copy (SMNc) encode the SMN protein, which is markedly reduced in SMA I patients. We have performed SMN transcript and protein studies on spinal cord sections of an SMA I patient using in situ hybridization and immunofluorescence. While the amount of protein was negligible, the level of transcripts was comparable with that of controls. These findings suggest that the reduced protein level is not caused by a deficient transcription of the SMNc gene.

Autoantigens↗

PubMed2001

Characterization of functional domains of the SMN protein in vivo.

The Survival of Motor Neurons (SMN) is the disease gene of spinal muscular atrophy. We have previously established a genetic system based on the chicken pre-B cell line DT40, in which expression of SMN protein is regulated by tetracycline, to study the function of SMN in vivo. Depletion of SMN protein is lethal to these cells. Here we tested the functionality of mutant SMN proteins by determining their capacity to rescue the cells after depletion of wild-type SMN. Surprisingly, all of the spinal muscular atrophy-associated missense mutations tested were able to support cell viability and proliferation. Deletion of the amino acids encoded by exon 7 of the SMN gene resulted in a partial loss of function. A mutant SMN protein lacking both the tyrosine/glycine repeat (in exon 6) and exon 7 failed to sustain viability, indicating that the C terminus of the protein is critical for SMN activity. Interestingly, the Tudor domain of SMN, encoded by exon 3, does not appear to be essential for SMN function since a mutant deleted of this domain restored cell viability. Unexpectedly, a chicken SMN mutant (DeltaN39) lacking the N-terminal 39 amino acids that encompass the Gemin2-binding domain also rescued the lethal phenotype. Moreover, the level of Gemin2 in DeltaN39-rescued cells was significantly reduced, indicating that Gemin2 is not required for DeltaN39 to perform the essential function of SMN in DT40 cells. These findings suggest that SMN may perform a novel function in DT40 cells.

Amino Acid Sequence↗

PubMed1994

Exonic trinucleotide repeats and expression of androgen receptor gene in spinal cord from X-linked spinal and bulbar muscular atrophy.

We studied exonic trinucleotide repeats and expression of androgen receptor (AR) gene in the spinal cord from an autopsied patient with X-linked spinal and bulbar muscular atrophy (SBMA). Forty-nine CAG triplet repeats were found in tissues from the spinal cord, cerebrum, cerebellum, cardiac muscle and bladder, while there were 20-24 CAG repeats in these tissues from control subjects, consisting of three patients with amyotrophic lateral sclerosis (ALS) and three patients with lung cancer. Thus, mitotic instability of the AR gene in SBMA may not occur at the level of somatic cells. To determine whether expression of the AR gene in the spinal cord of SBMA differs from that in control subjects, we used quantitative reverse transcriptase (RT)-PCR and Western blot. AR mRNA and protein were detected in the spinal cord from the patient with SBMA, but the levels of both AR mRNA and protein were less than those from the patients with ALS in whom the loss of motor neurons was similar to findings in the patient with SBMA. These findings suggest that structural alteration plus a reduced level of AR in the spinal cord are involved in the pathogenesis of SBMA, resulting in degeneration of motor neurons.

Adult↗

PubMed2006

[Two boys with non-progressive unilateral atrophy of the calf muscles].

We report here two boys who presented with atrophy of the right calf muscle. The onset was insidious and the symptom was found in infancy in case 2. They were followed for more than 5 years and no progression was seen. No sensory disturbances or autonomic nervous system symptoms were observed. Although needle electric myograph and muscle biopsy findings showed a neurogenic pattern, no cause was confirmed. Recently, a new disease concept of "benign monomelic amyotrophy of lower limb" was established and this could be applied to these patients. This disorder is rare and it is seen in young adults. It is characterized by non-progressive unilateral calf muscle atrophy. There is almost no possibility that this disorder is a variant of spinal muscular atrophy. When a patient presents with unilateral calf muscle atrophy, the treatable causes of the atrophy, including spinal cord disorders or peripheral nerve disorders, should be excluded first. If a confirmed cause cannot be found, then there should be a careful follow-up of the patient, even if the symptoms are stable.

Adolescent↗

PubMed1997

Expression study of survival motor neuron gene in human fetal tissues.

In order to investigate the spinal muscular atrophy (SMA) disease processes, the expression of the survival motor neuron gene (SMN) has been analyzed in human fetal tissues using RT-PCR and in situ hybridization. These studies allowed the detection of SMN RNA in all the examined tissues, with no significant variation between different developmental stages. In particular, SMN mRNA was detected in spinal cord (dorsal and ventral portions), skeletal muscle, lung, heart, kidney, liver, and spleen. Moreover, RT-PCR studies demonstrated that the expression pattern of SMN isoforms was similar to that observed in adult tissues. The present data confirm a housekeeping role for the SMN protein and may have implications on the search for early therapeutic strategies.

Cyclic AMP Response Element-Binding Protein↗

PubMed2002

Distinct expression of neuronal apoptosis inhibitory protein (NAIP) during murine development.

The childhood spinal muscular atrophies (SMAs) are autosomal recessive neurodegenerative conditions characterized by progressive degeneration of lower motor neurons. The gene encoding NAIP (neuronal apoptosis inhibitory protein) has been proposed to be a modulator of the severity of SMA and is frequently deleted in type I SMA. In this study we have assessed NAIP (murine homologue of NAIP) transcript levels during mouse embryogenesis. NAIP mRNA is present in the developing brain and spinal cord of E9.5-E14.5 mouse embryos as detected by various in situ hybridization techniques. It is also found in the embryonic branchial arches, the nasal epithelium and in the future digits. At E16.5, NAIP mRNA transcripts were found in the marginal zone of the lateral ventricle, the follicles of the vibrissae, in the retina and in the intestinal villi. These results are the first report of NAIP gene transcript levels in embryogenesis. If motor neuron attrition occurs in the second and third trimester of gestation in SMA, the observation of NAIP transcription in the mouse spinal cord between E9.5 and E14.5 is consistent with a role for NAIP in modifying this disorder.

Animals↗

PubMed1995

[Diagnostic studies in patients and relatives with hereditary neuromuscular diseases].

Preclinical and prenatal diagnosis as well as detection of healthy carriers is now theoretically possible for more than 200 monogenic inherited neurological and neuromuscular diseases and practically performed in many of them. However, it has to be made a condition, that the diagnosis in the index patient is secured by all clinical and laboratory methods available today, and that the specific mutation has been localized or even sequenced, and of course the families must give their full consent to the examinations. It is important to submit material for the different laboratory investigations from patients and their relatives as early as possible [biopsies, blood samples for DNA, etc.], at least for rapidly progressive diseases with a poor prognosis. In order to obtain very high probabilities in diagnostic predictions a family has to be examined either with mutation-specific DNA-probes and/or with probes for closely linked polymorphic DNA-markers. This requires a close cooperation between genetic services and DNA-laboratories on the one hand and the family doctors, specialists and clinics on the other. Specific strategies are discussed for hereditary sensory and motor neuropathy [HMSN la or Charcot-Marie-Tooth disease], Duchenne und Becker muscular dystrophy and childhood spinal muscular atrophies.

Charcot-Marie-Tooth Disease↗

PubMed2004

Hereditary motor and autonomic neuronopathy 1 maps to chromosome 20q13.2-13.3.

The spinal muscular atrophies (SMA) or hereditary motor neuronopathies result from the continuous degeneration and death of spinal cord lower motor neurons, leading to progressive muscular weakness and atrophy. We describe a large Brazilian family exhibiting an extremely rare, late-onset, dominant, proximal, and progressive SMA accompanied by very unusual manifestations, such as an abnormal sweating pattern, and gastrointestinal and sexual dysfunctions, suggesting concomitant involvement of the autonomic nervous system. We propose a new disease category for this disorder, 'hereditary motor and autonomic neuronopathy', and attribute the term, 'survival of motor and autonomic neurons 1' (SMAN1) to the respective locus that was mapped to a 14.5 cM region on chromosome 20q13.2-13.3 by genetic linkage analysis and haplotype studies using microsatellite polymorphic markers. This locus lies between markers D20S120 and D20S173 showing a maximum LOD score of 4.6 at D20S171, defining a region with 33 known genes, including several potential candidates. Identifying the SMAN1 gene should not only improve our understanding of the molecular mechanisms underlying lower motor neuron diseases but also help to clarify the relationship between motor and autonomic neurons.

Chromosome Mapping↗

PubMed1998

Heterogeneity of subcellular localization and electrophoretic mobility of survival motor neuron (SMN) protein in mammalian neural cells and tissues.

Spinal muscular atrophy is caused by defects in the survival motor neuron (SMN) gene. To better understand the patterns of expression of SMN in neuronal cells and tissues, we raised a polyclonal antibody (abSMN) against a synthetic oligopeptide from SMN exon 2. AbSMN immunostaining in neuroblastoma cells and mouse and human central nervous system (CNS) showed intense labeling of nuclear "gems," along with prominent nucleolar immunoreactivity in mouse and human CNS tissues. Strong cytoplasmic labeling was observed in the perikarya and proximal dendrites of human spinal motor neurons but not in their axons. Immunoblot analysis revealed a 34-kDa species in the insoluble protein fractions from human SY5Y neuroblastoma cells, embryonic mouse spinal cord cultures, and human CNS tissue. By contrast, a 38-kDa species was detected in the cytosolic fraction of SY5Y cells. We conclude that SMN protein is expressed prominently in both the cytoplasm and nucleus in multiple types of neurons in brain and spinal cord, a finding consistent with a role for SMN as a determinant of neuronal viability.

Animals↗

PubMed2026

The SMN locus in the T2T era: Structure, gene conversion, and clinical implications.

Long-read sequencing, paralog-aware variant calling, and telomere-to-telomere (T2T) human genome assemblies now enable the resolution of copy-, haplotype-, and nucleotide-level complexities in segmentally duplicated loci, which were previously inaccessible with short-read sequencing. In this review, we highlight how current technologies and analysis methods reveal extensive diversity in copy number (CN), structure, and gene conversion within the spinal muscular atrophy-associated survival motor neuron (SMN) locus. We summarize how understanding population-level structural variation could be translated into clinical practice, where a nucleotide-level view of the SMN locus may refine prognostic accuracy beyond SMN2 CN and explain variable treatment responses. Finally, we discuss how the approaches and methodologies required to study the SMN locus may be applied elsewhere, providing a scaffold to characterize other complex human genetic regions.

Humans↗