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PubMed2003

Patients with severe muscle wasting are prone to develop hypoglycemia during fasting.

The authors investigated whether hypoglycemia develops during 23 hours of fasting in patients with Duchenne dystrophy (7 patients), spinal muscular atrophy (4 patients), and congenital myopathy (2 patients), all with residual muscle mass <10% of body weight. All patients with spinal muscular atrophy and congenital myopathy and one patient with Duchenne dystrophy, but none of six healthy subjects, developed hypoglycemia. Skeletal muscle is an important source of gluconeogenic substrates during fasting. Hypoglycemia must be considered in patients with low muscle mass, especially during surgery and febrile episodes.

Adult↗
PubMed2006

Loss of endogenous androgen receptor protein accelerates motor neuron degeneration and accentuates androgen insensitivity in a mouse model of X-linked spinal and bulbar muscular atrophy.

X-linked spinal and bulbar muscular atrophy (SBMA; Kennedy's disease) is a polyglutamine (polyQ) disease in which the affected males suffer progressive motor neuron degeneration accompanied by signs of androgen insensitivity, such as gynecomastia and reduced fertility. SBMA is caused by CAG repeat expansions in the androgen receptor (AR) gene resulting in the production of AR protein with an extended glutamine tract. SBMA is one of nine polyQ diseases in which polyQ expansion is believed to impart a toxic gain-of-function effect upon the mutant protein, and initiate a cascade of events that culminate in neurodegeneration. However, whether loss of a disease protein's normal function concomitantly contributes to the neurodegeneration remains unanswered. To address this, we examined the role of normal AR function in SBMA by crossing a highly representative AR YAC transgenic mouse model with 100 glutamines (AR100) and a corresponding control (AR20) onto an AR null (testicular feminization; Tfm) background. Absence of endogenous AR protein in AR100Tfm mice had profound effects upon neuromuscular and endocrine-reproductive features of this SBMA mouse model, as AR100Tfm mice displayed accelerated neurodegeneration and severe androgen insensitivity in comparison to AR100 littermates. Reduction in size and number of androgen-sensitive motor neurons in the spinal cord of AR100Tfm mice underscored the importance of AR action for neuronal health and survival. Promoter-reporter assays confirmed that AR transactivation competence diminishes in a polyQ length-dependent fashion. Our studies indicate that SBMA disease pathogenesis, both in the nervous system and the periphery, involves two simultaneous pathways: gain-of-function misfolded protein toxicity and loss of normal protein function.

Androgen-Insensitivity Syndrome↗
PubMed1992

Predictive value of electromyography in diagnosis and prognosis of the hypotonic infant.

To investigate the diagnostic validity of electromyography in the hypotonic infant, 79 children aged 0 to 12 months, seen over a 20-year period, were studied retrospectively. The diagnoses using clinical, muscle biopsy, and laboratory characteristics were: 25 central hypotonia, 20 spinal muscular atrophy, 20 myopathy, four myotonic dystrophy, four benign congenital hypotonia, two congenital muscular dystrophy, two myasthenia gravis, one infantile inflammatory myopathy, and one arthrogryposis multiplex congenita. Using strict criteria, electromyography accurately predicted the final diagnosis in 65% of infants with spinal muscular atrophy and was consistent with the diagnosis in another 25%. In contrast, electromyography accurately predicted the final diagnosis in only 10% of infants with myopathy and was normal in 88% of infants with central hypotonia. In infants with spinal muscular atrophy, there was no difference in the predictive value of electromyography when performed in the newborn compared to older infants. Normal distal nerve conduction velocities in infants with spinal muscular atrophy may predict prognosis, since these infants had a longer survival. Electromyography thus has a high predictive value for infantile spinal muscular atrophy but not for myopathy.

Biopsy↗
PubMed2006

SMN, the product of the spinal muscular atrophy-determining gene, is expressed widely but selectively in the developing human forebrain.

The expression pattern of the survival motor neuron (SMN) protein has been investigated immunohistochemically in the human fetal forebrain from 14 to 38 weeks of gestation. Mutations in the SMN gene cause spinal muscular atrophy (SMA), an autosomal recessive disease characterized by degeneration of lower motor neurons in the spinal cord leading to progressive muscle wasting. SMN is a multifunctional protein and has been implicated in diverse cytoplasmic and nuclear processes. The monoclonal murine SMN antibody used in this study recognized a major band at approximately 34 kDa. In spinal cord anterior horn motor neurons at 13 weeks of gestation, the soma, proximal neurites, and nucleus were immunostained. In the nucleus, SMN immunolabeling was observed at the nuclear membrane, at the nucleolus, and at dot-like structures in the nucleoplasm likely to be coiled bodies and gems. In the fetal forebrain, SMN was immunodetected as early as 14 weeks of gestation. From 14 to 24 weeks of gestation, intense immunostaining was observed in the basal nucleus of Meynert, a major source of cholinergic afferents to the cortex. Less intensely labeled cells at lower packing density were also observed in the thalamus, reticular and perireticular nucleus, globus pallidus, hippocampus, amygdala, and enthorinal cortex. Immunolabeled cells were still detectable at 38 gestational weeks, the latest time point investigated. These findings provide an anatomical basis for future investigations of SMN functions during brain development and for the neuropathological characterization of severe SMA cases.

Anterior Horn Cells↗
PubMed1988

[Sonographic detection of fasciculations].

Fasciculations are an important neurological sign of spinal muscular atrophies. 26 patients able to walk suffering from adult onset spinal muscular atrophies were examined by real time sonography. On an average 18 limb and extremity muscles on both sides were examined. In 21 cases fasciculations became sonographically apparent as muscular twitchings lasting for 0.2 to 0.5 seconds. Detection of fasciculations in profound muscular layers and in obese patients was easier by sonography than by clinical examination.

Adult↗
PubMed1997

[Neurological CPC.57. An 80-year-old woman with four years history of muscle atrophy involving lower extremities predominantly on the right side].

We report an 80-year-old woman with progressive muscular atrophy predominantly involving her right lower extremity. She was well until 1992 (75 years of age) when she noted an onset of weakness in her right leg which had got progressively worse. She was admitted to our service in July 1994. On admission, general physical examination was unremarkable. She was alert and well oriented without dementia. Higher cerebral functions were normal. Cranial nerves also appeared intact. She dragged her right leg in walking. Mild to moderate weakness (2/5 to 4/5) was noted in muscles in her right lower extremity more in the distal part. Deep tendon reflexes were within normal limits, and the plantar response was flexor bilaterally. Sensation was intact. Laboratory examinations were also unremarkable except for slight increase in CK which was 470 IU/l. CSF was also normal. EMG revealed neurogenic changes in the lower extremities. She was admitted to Aoki Hospital on October 21, 1994, by that time, her weakness in the right lower extremity had gotten worse in that the muscle strength of the right extensor hallucis longus was 0 and tibialis anterior 2; muscle atrophy was also prominent in her right leg; the right ankle jerk could not be elicited. In the subsequent course, weakness and atrophy appeared in her left lower extremity, however, upper extremities and cranial nerves had never been affected. Babinski sign was always negative. In February 1996, she developed delusional ideation of self persecution, and showed difficulty in communication with medical staffs. She developed fever of 38.7 degrees C on June 13, 1996 expired on the next day. The patient was discussed in a neurological CPC, and the chief discussant arrived at the conclusion that the patient had a form of spinal muscular atrophy. Opinions were divided between ALS and spinal muscular atrophy. Post-mortem examination revealed marked loss of anterior horn neurons in the lumbar area with astrogliosis. Bunina bodies were seen in some of the remaining neurons. No myelin pallor was noted in the pyramidal tracts, however, atrophy and loss of Betz cells were noted in the motor cortex. Other cortical areas were unremarkable. The neuropathologist arrived at the conclusion that the patient had ALS. This patient was unique in that she had asymmetric atrophy and weakness limited to the lower extremities. This is quite unusual as ALS of four years duration. In addition, the patient developed some mental change which was thought to represent dementia by some participants. But no clear morphologic changes were seen to account for her mental change.

Aged↗
PubMed2001

Structural and functional alterations in the androgen receptor in spinal bulbar muscular atrophy.

The androgen receptor is a member of the nuclear receptor superfamily, and regulates gene expression in response to the steroid hormones testosterone and dihydrotestosterone. Mutations in the receptor have been correlated with a diverse range of clinical conditions, including androgen insensitivity, prostate cancer and spinal bulbar muscular atrophy, a neuromuscular degenerative condition. The latter is caused by expansion of a polyglutamine repeat within the N-terminal domain of the receptor. Thus the androgen receptor is one of a growing number of neurodegenerative disease-associated proteins, including huntingtin (Huntington's disease), ataxin-1 (spinocerebellar ataxia, type 1) and ataxin-3 (spinocerebellar ataxia, type 3), which show expansion of CAG triplet repeats. Although widely studied, the functions of huntingtin, ataxin-1 and ataxin-3 remain unknown. The androgen receptor, which has a well-recognized function in gene regulation, provides a unique opportunity to investigate the functional significance of poly(amino acid) repeats in normal and disease states.

Animals↗
PubMed2001

Preimplantation genetic diagnosis for spinal and bulbar muscular atrophy (SBMA).

X-linked spinal and bulbar muscular atrophy is characterized by adult onset motor neuron disease and results from a defect in the androgen receptor. The disease is caused by a dynamic mutation in the first exon of the androgen receptor gene, involving a CAG trinucleotide repeat. We have developed a single-cell polymerase chain reaction assay for the androgen receptor gene and describe the application of this assay for preimlantation genetic diagnosis (PGD) in a couple at risk, where the female partner is a carrier of 47 repeats. Diagnosis was based on the detection of both normal and expanded alleles. Allele dropout of the expanded allele was observed in only 1 of 25 lymphoblasts of the carrier and of a non-expanded allele in 1 of 20 research blastomeres tested before the actual PGD. One contraction of four repeats was also found in the carrier's lymphoblasts. Neither expansions nor contractions were observed in the blastomeres biopsied from 11 embryos. Two embryos were unaffected, eight were female carriers and one was an affected male embryo.

Alleles↗
PubMed1996

Mitotic and meiotic stability of the CAG repeat in the X-linked spinal and bulbar muscular atrophy gene.

X-linked spinal and bulbar muscular atrophy (SBMA) occurs due to an expansion of the trinucleotide repeat (CAG)n in the androgen receptor gene. Anticipation is relatively rare in SBMA in contrast to spinocerebellar ataxia type 1 (SCAl), and dentatorubral and pallidoluysian atrophy (DRPLA) which show obvious paternal anticipation. The differences in the CAG repeat number were compared among sperm, leukocytes and skeletal muscles of SBMA patients. In SBMA, the sperm of most patients and the skeletal muscle of all patients showed the same repeat number as their leukocytes, whereas the increase in the repeat number from leukocytes to sperm was evident in SCA1 and DRPLA patients. The higher mosaicism level in sperm compared with leukocytes was common in SBMA, SCA1 and DRPLA, and the level of sperm was lower in SBMA than in SCA1 and DRPLA. Thus, spermatogenesis was suggested to be strongly associated with paternal anticipation. The mosaicism level was smaller in SBMA than in other (CAG)n expanded disorders, and smallest in the SBMA carrier females. These findings demonstrate that the CAG repeat in SBMA is relatively stable in mitotic and meiotic, processes, and there is a possibility that the lower mosaicism level of the carrier females compared with the SBMA patients is associated with X-linked recessive inheritance.

Female↗
PubMed1983

Unilateral scapulohumeral muscular atrophy.

A peculiar form of chronic spinal muscular atrophy is described, 5 unrelated young males developed muscle wasting of the left shoulder and upper arm region, mainly in the distribution of myotomes C5 and C6. This muscle atrophy remained confined to the primary site for 13-18 years, being followed in 4 cases by a mild muscle atrophy of the right upper arm or or the left forearm and hand and in 1 case by atrophy of the legs and the facial muscles. On EMG examination, muscle involvement was always found to be more widespread than on clinical examination. The repeated and extensive EMG examinations gave results typical of an anterior horn cell disease. Pyramidal signs were absent. During the observation period of 21-40 years the course was benign and at least partial working capacity was retained until retiring age.

Aged↗
PubMed2002

Autosomal dominant juvenile amyotrophic lateral sclerosis and distal hereditary motor neuronopathy with pyramidal tract signs: synonyms for the same disorder?

Autosomal dominant juvenile amyotrophic lateral sclerosis (ALS) is a rare disorder and so far only one family has been reported. Genetic linkage studies mapped the disease locus to chromosome 9q34 (ALS4). The diagnosis of ALS in this family is based on the clinical signs with almost exclusively lower motor neurone pathology in combination with less prominent pyramidal tract signs. Atypical features include normal life expectancy, the absence of bulbar involvement and the symmetrical distal distribution of atrophy and weakness. We performed a molecular genetic study in three families that we had diagnosed as having distal hereditary motor neuronopathy, i.e. distal spinal muscular atrophy or spinal Charcot-Marie-Tooth syndrome, and found linkage to the ALS4 locus. The clinical phenotype in these three families, of different geographic origin (Austria, Belgium and England), is strikingly similar to the autosomal dominant juvenile ALS family except for a younger onset age in two of the distal hereditary motor neuronopathy families. These data suggest that ALS4 and distal hereditary motor neuronopathy with pyramidal tract signs may be one and the same disorder.

Adolescent↗
PubMed1985

Non-familial, spinal segmental muscular atrophy in juvenile and young subjects.

Thirty-two cases of juvenile and adult onset, non-familial, spinal, segmental muscular atrophy seen in two widely separated geographical regions of India were studied over the last 15 years. The characteristic features were: the non-familial, non-endemic nature, the strictly segmental distribution from the clinical and EMG point of view, which involved either distal or proximal segments of one upper or lower extremity, the absence of involvement of cranial nerves of the pyramidal, sensory and autonomic nervous system, the very high male predilection and the very insidious progression. No definitive etiological factors could be incriminated.

Adult↗
PubMed1987

Nemaline bodies in spinal progressive muscular atrophy. An autopsy case.

Numerous nemaline bodies were demonstrated in the pectoralis major muscle of an autopsy case of a 52-year-old woman, who died of respiratory failure after having suffered from spinal progressive muscular atrophy for 1 year. Rod-like structures ultrastructurally indistinguishable from classical nemaline bodies were abundant in both normal-appearing and atrophic myofibers of the pectoralis major muscle but not in the appendicular skeletal muscles. Morphometric analysis of spinal anterior horn cells clearly showed severe depopulation of somatic motor neurons in the lower cervical cord segments. The present case may provide further support for the neurogenic nature of nemaline body formation.

Female↗
PubMed1996

The paralysé mouse mutant: a new animal model of anterior horn motor neuron degeneration.

The survival and morphometric characteristics of lumbar spinal motoneurons were examined in the paralysé mouse mutant. Affected (par/par) mice can be first recognized at approximately postnatal day (PN) 7 to 8 and are characterized by their smaller-than-normal body size, a progressive generalized muscle weakness, and lack of coordination. Mutant mice die by PN16-18, when they have become almost completely paralyzed. Previously, we have shown that this mutation involves alteration of several developmental aspects of the neuromuscular system. However, whether ventral (or anterior) horn motoneurons degenerate and die during the course of the disease was unknown. We report here that at the time the mutant phenotype can be first identified (i.e. approximately PN8), lumbar motoneuron numbers in the lateral motor column of the spinal cord of paralysé mice were not significantly different from those of control littermates. In contrast, by PN14, there was a significant (30 to 35%) decrease in motoneuron numbers in mutant compared to control mice. Furthermore, motoneuron (nuclear and soma) sizes were significantly decreased in the mutants at both stages examined, i.e. PN8 and PN14. These results show that the paralysé mutation involves atrophy and subsequent death of anterior horn motoneurons. Together with the rapid progression and the severity of the disease, these results suggest that the paralysé mouse may represent a good animal model for studying early-onset human motor neuron diseases such as spinal muscular atrophy.

Animals↗
PubMed1978

Patterns of abnormal histochemical fibre type differentitation in human muscle biopsies.

The histochemical profile of individual human skeletal muscle fibres was analysed by correlating mitochondrial oxidative enzyme activity and that of myofibrillar ATPase at pH 9.5 and after pre-incubation at pH 4.3 and pH 4.6. In normal control muscle, only a small percentage of fibres did not conform to one or other of the normal variants of Type I and Type II fibres. In biopsies from early cases of Werdnig-Hoffmann disease, the denervated fibre populations contained many abnormal Type I and Type II fibres, including "IIc" fibres, but the basic distinction between Type I and Type II was preserved. However, in infantile spinal muscular atrophy patients aged two years and over, this distinction was progressively lost, leading to the total dedifferentiation of the atrophied fibres. In the Kugelberg-Welander form of spinal muscular atrophy, many of the constituent fibres of re-innervated groups displayed normal or near-normal histochemical profiles, but chronically denervated fibres became totally dedifferentiated. In Duchenne dystrophy, the spectrum of histochemical types appeared to be more continuous due to the emergence of fibres with properties intermediate between those of the normal variants, but the basic distinction between Type I and Type II fibres was preserved in the majority of cases. The percentage of severely abnormal fibres was higher in Type II than Type I and probably contributed to the observed decrease in the overall proportion of Type II fibres. Although very small atrophied fibres were observed in biopsies from cases of Becker and Duchenne dystrophy, these did not show the total dedifferentiation seen in the chronically denervated fibres in cases of spinal muscular atrophy.

Adenosine Triphosphatases↗
PubMed2006

Expanding the phenotypes of the Pro56Ser VAPB mutation: proximal SMA with dysautonomia.

The phenotype of 16 members of a family affected by a late-onset, dominant, progressive, motor and autonomic disorder is described. The VAPB (Pro56Ser) mutation was detected in Brazilian families with different phenotypes of motor neuron disorders. In this family, proximal and axial muscle weakness and atrophy, associated with abdominal protrusion, defined the motor phenotype. Death occurred in 10-15 years due to respiratory insufficiency. Tone and tendon reflexes were decreased and a distal tremor was common. Sensation was preserved. Autonomic abnormalities were also present, including choking, chronic intestinal constipation, sexual dysfunction, and sudomotor abnormalities, and on nerve morphology there was involvement of unmyelinated fibers. Electromyography disclosed ongoing denervation and reinnervation. Isolated dysfunction of motor and autonomic neurons is unusual among the spinal muscular atrophies. On this basis, this condition seems to represent a new category of disease.

Adult↗