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PubMed1998

Truncated forms of the androgen receptor are associated with polyglutamine expansion in X-linked spinal and bulbar muscular atrophy.

X-linked spinal and bulbar muscular atrophy (SBMA) is a rare form of motor neuron degeneration linked to a CAG repeat expansion in the first exon of the androgen receptor gene coding for a polyglutamine tract. In order to investigate the properties of the SBMA androgen receptor in neuronal cells, cDNAs coding for a wild-type (19 CAG repeats) and a SBMA mutant androgen receptor (52 CAG repeats) were transfected into mouse neuroblastoma NB2a/d1 cells. The full length androgen receptor proteins, of 110-112 kDa and 114-116 kDa for the wild-type and mutant protein, respectively, were detected by Western blotting in transfected cells. In addition, the presence of an expanded polyglutamine tract in the SBMA androgen receptor appears to enhance the production of C-terminally truncated fragments of the protein. A 74 kDa fragment was particularly prominent in cells expressing the SBMA androgen receptor. From its size, it can be deduced that the 74 kDa fragment lacks the hormone binding domain but retains the DNA binding domain. The 74 kDa fragment may therefore be toxic to motor neurons by initiating the transcription of specific genes in the absence of hormonal control. Immunofluorescence microscopy on transfected NB2a/d1 cells showed that, after hormone activation, the wild-type androgen receptor translocated to the nucleus whereas the SBMA androgen receptor was mainly localized in the cytoplasm in the form of dense aggregates with very little androgen receptor protein in the nucleus. This could explain the reduction in transcriptional activity of the SBMA mutant as compared with wild-type androgen receptor.

Animals↗
PubMed1997

Pattern of motor neurone disease in eastern India.

A clinical study about the pattern of motor neurone disease in eastern India was carried out from July 1993 to June 1995 at Bangur Institute of Neurology, Calcutta and SSKM Hospital, Calcutta. A total of 110 cases were studied and they constituted 0.11% of all neurological cases seen in the general OPD. Of 110 cases, amyotropic lateral sclerosis (ALS) constituted 43.6%, progressive muscular atrophy (PMA) 10.9%, post-polio progressive muscular atrophy (PPMA) 1.8%, spinal muscular atrophy (SMA) 20%, atypical form Madras pattern of MND (MMND) 0.9% and monomelic amyotrophy (MMA) 22.7% of cases. Disease is more common in males than females and average duration of symptoms before presentation varied from 1 to 12 months. Most of the patients were either agricultural labourers or manual workers in ALS variety whereas MMA variety was evenly distributed in both hard labourers and sedentary workers. Most of the patients in MMA and SMA groups presented before 30 years of age whereas ALS and PMA group presented after 30 years. Trauma was the commonest antecedent event in ALS and MMA followed by electrocution in the same two groups. Family history was found to be absent in SMA group though the disease is considered as a hereditary one. Weakness of the limbs and wasting of the muscles were common presenting symptoms and signs. Bulbar symptoms and signs were found only in the ALS group. EMG showed neurogenic pattern and mixed pattern in most of the patients in all groups. Only a few patients showed myopathic pattern. Neuroimaging study helped in exclusion of compressive lesion excepting two cases of MMA where facetal hypertrophy was present. Monomelic amyotrophy, a special variety of motor neurone disease, is not rare in this part as compared to other parts of India and Asia.

Female↗
PubMed1992

Strong correlation between the number of CAG repeats in androgen receptor genes and the clinical onset of features of spinal and bulbar muscular atrophy.

X-linked spinal and bulbar muscular atrophy (SBMA), a motor neuron disease associated with androgen insensitivity, is caused by androgen receptor gene mutations with an increased number of tandem CAG repeats in exon 1. We investigated the increased number of CAG repeats in androgen receptor genes of 19 SBMA patients and found that this correlated strongly with the age at onset of muscle weakness. Thus, SBMA is the first genetic disease in which a strong correlation between the degree of genetic abnormality (number of CAG tandem repeats) and clinical phenotypic expression is demonstrable. The results further indicate that androgen gene mutation is directly involved in the degeneration of motor neurons.

Adult↗
PubMed1993

[A novel primer extension method to detect the number of CAG repeats in the androgen receptor gene in families with X-linked spinal and bulbar muscular atrophy].

X-linked spinal and bulbar muscular atrophy (SBMA), an adult-onset form of motor neuron disease, was recently reported to be caused by amplification of the CAG repeats in the androgen receptor gene. We report here a simple and rapid strategy to detect the precise number of the CAGs. After the DNA fragment containing the CAG repeats is amplified by the polymerase chain reaction, a primer extension is carried out; the extension of the end-labelled reverse primer adjacent to 3' end of CAG repeats stops at the first T after CAG repeats with the incorporation of dideoxy ATP in the reaction mixture. The resultant primer products are analysed by denaturing polyacrylamide gel electrophoresis and autoradiography. This method could be quite useful to detect not only CAG repeats in SBMA but also other polymorphic dinucleotide and trinucleotide repeats.

Adolescent↗
PubMed2004

Homozygous SMN1 deletions in unaffected family members and modification of the phenotype by SMN2.

Spinal muscular atrophy is a common autosomal recessive neuromuscular disorder caused by the homozygous loss of the SMN1 gene. The absence of the SMN1 gene has been shown to occur in all types of SMA, childhood and adult forms. In rare cases, asymptomatic family members have also been found with homozygous mutations in the SMN1 gene, suggesting a role for phenotypic modifiers. We describe three unrelated asymptomatic individuals, with family histories of SMA, who were shown to have the homozygous SMN1 deletion. Quantitative studies indicated that the three individuals all had increased SMN2 copy numbers. These cases not only support the role of SMN2 in modifying the phenotype, but our data also demonstrate that expression levels consistent with five copies of the SMN2 genes maybe enough to compensate for the absence of the SMN1 gene. Lastly, in cases similar to the ones described, the measurement of the SMN2 gene copy number may provide valuable prognostic information.

Adult↗
PubMed2003

Mitral valve surgery in a patient with spinal progressive muscular atrophy: report of a case.

We describe our experience in treating a 69-year-old man with spinal progressive muscular atrophy (SPMA), who underwent a mitral valve replacement. He was admitted for dyspnea, and surgery was indicated for severe mitral insufficiency associated with inferior myocardial infarction. He had been aware of muscle weakness and received a diagnosis of SPMA 18 years previously. Worsening muscle atrophy had led to the need for him to use a wheelchair in his daily life. A preoperative examination revealed markedly reduced pulmonary function (% volume capacity = 44.8%). Because of an acute exacerbation of heart failure, the patient underwent an urgent mitral valve replacement with a 27-mm pericardial bioprosthesis. Although it took 42h to wean him from the mechanical ventilation and he suffered from pulmonary atelectasis after extubation, he was discharged from our hospital in a wheelchair 16 days after surgery. Respiratory management with bilevel positive airway pressure was thus found to be quite useful for patients with neuromuscular disease.

Aged↗
PubMed2003

Determination of SMN1 and SMN2 copy number using TaqMan technology.

Infantile spinal muscular atrophy (SMA) is a neuromuscular disease caused by homozygous deletion of the SMN1 gene in more than 90% of patients. Identification of carriers for the SMN1 deletion is important for diagnostic purposes and for genetic counseling. The current practical implications of SMN2 copy number determination are limited but may be important, for example, for future drug trials. Here we present a new rapid and reliable approach to determine the copy numbers of the SMN1 and SMN2 genes: For differentiation of the two genes, we developed a quantitative test on the basis of TaqMan technology using minor groove binder (MGB) probes. To evaluate the approach in respect to detection of SMN1 deletion carriers, we tested 40 putative carriers as well as 100 controls. We confirmed the carrier status in all individuals; furthermore, the distribution of SMN1 and SMN2 copies in the control cohort corresponded to that published previously. In total, a clear-cut differentiation between the different copy number ranges could be observed for both genes. This distinct differentiation is based on the exact specificity of MGB probes and the parallel analysis of an external reference locus that circumvents the problem of unavoidable deviations in DNA concentrations. The simplicity and reproducibility of the TaqMan assay presented here should facilitate its establishment in molecular diagnostic laboratories. Nevertheless, the applicability of quantitative analyses of SMN copy numbers requires knowledge about its options and limitations, based on the complex nature of the SMN region and the clinical variability of SMA. Therefore, determination of SMN1 and SMN2 copy numbers should only be offered after careful consideration in each case.

Cyclic AMP Response Element-Binding Protein↗
PubMed2003

Smn, the spinal muscular atrophy-determining gene product, modulates axon growth and localization of beta-actin mRNA in growth cones of motoneurons.

Spinal muscular atrophy (SMA), a common autosomal recessive form of motoneuron disease in infants and young adults, is caused by mutations in the survival motoneuron 1 (SMN1) gene. The corresponding gene product is part of a multiprotein complex involved in the assembly of spliceosomal small nuclear ribonucleoprotein complexes. It is still not understood why reduced levels of the ubiquitously expressed SMN protein specifically cause motoneuron degeneration. Here, we show that motoneurons isolated from an SMA mouse model exhibit normal survival, but reduced axon growth. Overexpression of Smn or its binding partner, heterogeneous nuclear ribonucleoprotein (hnRNP) R, promotes neurite growth in differentiating PC12 cells. Reduced axon growth in Smn-deficient motoneurons correlates with reduced beta-actin protein and mRNA staining in distal axons and growth cones. We also show that hnRNP R associates with the 3' UTR of beta-actin mRNA. Together, these data suggest that a complex of Smn with its binding partner hnRNP R interacts with beta-actin mRNA and translocates to axons and growth cones of motoneurons.

3' Untranslated Regions↗
PubMed2006

Determination of SMN1/SMN2 gene dosage by a quantitative genotyping platform combining capillary electrophoresis and MALDI-TOF mass spectrometry.

BACKGROUND: Spinal muscular atrophy (SMA) is a common inherited and fatal neuromuscular disease caused by deletions and/or mutations that lead to altered concentrations of proteins encoded by the survival motor neuron genes SMN1 and SMN2. Because of the high incidence (at least 1 in 10,000 live births and a carrier frequency of 1 in 35 to 1 in 50) and severity of the disease, precise quantification of SMN1 and SMN2 gene copy numbers is essential for diagnosis and genetic counseling. METHODS: We developed a genotyping platform combining capillary electrophoresis and matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) to quantify absolute gene dosage. The absolute gene dosage can be determined by a multiplexed competitive PCR protocol followed by capillary electrophoresis analysis. The relative SMN1/SMN2 ratio can be analyzed by PinPoint assay followed by MALDI-TOF MS analysis. RESULTS: The complementary assays were evaluated in confirmed cases including 9 affected patients, 33 carriers, and 478 healthy individuals from the general population. We were able to determine all genotypes with different SMN1/SMN2 gene copy number ratios, which unambiguously diagnosed carrier status and the severity of SMA with 100% specificity. CONCLUSIONS: This quantitative genotyping platform is suitable for detection of SMA. The described approach may serve as a general quantitative genotyping method for molecular diagnosis of other inheritable diseases.

Cyclic AMP Response Element-Binding Protein↗
PubMed2002

X-linked spinal and bulbar muscular atrophy without proximal atrophy.

We report on a case of genetically proven X-linked spinal and bulbar muscular atrophy (X-SBMA) with prominent distal muscle atrophy and without proximal muscle involvement. The patient was a 35-year-old man who had a history of slow progressive hand and distal leg muscle weakness and wasting for 10 years. Motor nerve conduction velocities were normal with reduced compound muscle action potential amplitudes of hand and foot muscles. Sensory action potential amplitudes were small. Needle EMG revealed a chronic partial denervation with reduced interference in hand and distal leg muscles but with normal heading in all tested proximal muscles. Genetic studied showed an expansion of CAG repeat in the first exon of the androgen receptor gene, which suggests diagnosis of X-SBMA. The importance of genetic studies in this patient with unusual clinical presentation is emphasized.

Adult↗
PubMed2005

Phenotypic spectrum of disorders associated with glycyl-tRNA synthetase mutations.

We describe clinical, electrophysiological, histopathological and molecular features of a unique disease caused by mutations in the glycyl-tRNA synthetase (GARS) gene. Sixty patients from five multigenerational families have been evaluated. The disease is characterized by adolescent onset of weakness, and atrophy of thenar and first dorsal interosseus muscles progressing to involve foot and peroneal muscles in most but not all cases. Mild to moderate sensory deficits develop in a minority of patients. Neurophysiologically confirmed chronic denervation in distal muscles with reduced compound motor action potentials were features consistent with both motor neuronal and axonal pathology. Sural nerve biopsy showed mild to moderate selective loss of small- and medium-sized myelinated and small unmyelinated axons, although sensory nerve action potentials were not significantly decreased. Based on the presence or absence of sensory changes, the disease phenotype was initially defined as distal spinal muscular atrophy type V (dSMA-V) in three families, Charcot-Marie-Tooth disease type 2D (CMT2D) in a single family, and as either dSMA-V or CMT2D in patients of another large family. Linkage to chromosome 7p15 and the presence of disease-associated heterozygous GARS mutations have been identified in patients from each of the five studied families. We conclude that patients with GARS mutations present a clinical continuum of predominantly motor distal neuronopathy/axonopathy with mild to moderate sensory involvement that varies between the families and between members of the same family. Awareness of these overlapping clinical phenotypes associated with mutations in GARS will facilitate identification of this disorder in additional families and direct future research toward better understanding of its pathogenesis.

Adolescent↗
PubMed2005

Emerging pathways for hereditary axonopathies.

Motor neurons are affected in a number of neurological diseases. Their unifying pathological signature is degeneration of extended projecting axons and loss of motor neurons in the prefrontal cortex and/or the spinal cord. Based on clinical criteria, hereditary forms have been traditionally divided into distinct entities, such as familial amyotrophic lateral sclerosis, hereditary motor neuropathy, spinal muscular atrophy, familial spinal paraplegia, and Charcot-Marie-Tooth disease type 2, also known as hereditary motor and sensory neuropathy II. Genetic research of the last decade has revealed remarkable heterogeneity within these disorders. Most of the identified genes to date cause disease in a classic Mendelian inheritance pattern with a high phenotypic penetrance. This rich source of molecular genetic data has already provided insight into the underlying major pathways of these diseases and should continue to do so in the future. This review attempts to cross the traditional clinical classifications in order to draw an emerging picture of common pathways between causative genes, providing a different perspective of this rapidly growing scientific field.

Amyotrophic Lateral Sclerosis↗
PubMed2004

Neurologic course, endocrine dysfunction and triplet repeat size in spinal bulbar muscular atrophy.

OBJECTIVE: To study the role of diabetes, gynecomastia and CAG triplet repeat size as disease modifying factors of neurologic expression in spinal bulbar muscular atrophy (SBMA, Kennedy's disease). METHODS: Twenty unrelated SBMA patients with confirmatory genetic testing were reviewed. Patterns of neurologic involvement were assessed (e.g. bulbar, asymmetric, proximal, distal, motor and sensory). Slopes of disease progression were calculated from serial quantified neurologic examinations. Patterns of neurologic involvement and course were correlated to the presence of diabetes, gynecomastia and triplet repeat size. RESULTS: Diabetes or glucose impairment occurred in nine and 11 had gynecomastia. Patterns of neurologic involvement and rates of progression did not correlate with these endocrine diseases or triplet repeat sizes. Correlation was seen between number of CAG repeats and age of onset weakness (r = -0.53, r2 = 29%, p = 0.01). CONCLUSIONS: The specific neurotoxic effect of expanded CAGs appears limited to age of onset weakness in SBMA. Although significant, only 29% of the variability in onset age could be accounted for by polyglutamine size suggesting the importance of other unidentified factors. In this series diabetes or glucose impairment was more common than previously reported and, like gynecomastia, did not correlate with size of triplet repeats, severity or patterns of neurologic involvement. Modifying factors other than diabetes, gynecomastia or triplet repeat size are suggested in disease expression.

Adult↗
PubMed2004

Sporadic amyotrophic lateral sclerosis of long duration mimicking spinal progressive muscular atrophy exists: additional autopsy case with a clinical course of 19 years.

This report concerns an autopsy case of sporadic amyotrophic lateral sclerosis (ALS) clinically diagnosed as having spinal progressive muscular atrophy (SPMA). The patient was a Japanese woman without hereditary burden. She developed muscle weakness in the distal part of the right upper extremity at age 52, followed by muscle weakness in the left upper extremity and lower extremities at age 54 and 64, respectively. At age 66 she could not walk, even with assistance. Fasciculation and atrophy of the tongue appeared at age 68, followed by dysphagia and dysarthria at age 70. She died of respiratory disturbance at age 71. During the clinical course, neurological examination revealed neither Babinski sign nor hyperreflexia. No respirator administration was performed throughout the clinical course. Neuropathological examination disclosed not only neuronal loss with gliosis in the hypoglossal nucleus and anterior horns of the spinal cord, but also loss of Betz cells and degeneration of the pyramidal tract. Based on these clinicopathological findings and a literature review of sporadic autopsy cases of ALS with long clinical course (10 years or more), including four cases without pyramidal signs, we believe that sporadic ALS of long clinical course mimicking SPMA exists.

Aged↗
PubMed1988

[Nerve growth factors: a hypothesis on their role in the pathogenesis of infantile spinal amyotrophies].

The spinal muscular atrophies (SMA) are inherited neurological disorders characterized by degeneration and atrophy of spinal motoneurons at infant and juvenile stages. The origin of these diseases, and the mechanism of their progression, are completely unknown. Nevertheless, the selective neuronal loss which characterizes them is reminiscent of a classical experimental observation: injection of antibodies to the Nerve Growth Factor (NGF) in neonatal rats results in the almost complete selective destruction of the sympathetic nervous system. NGF is one of a group of molecules, the neuronal growth factors, which most likely play a role in the regulation of neuron number and development in different parts of the nervous system. In particular, several in vivo and in vitro results suggest that muscle may at certain stages produce "motoneuron growth factors". Our hypothesis is that the motoneuron death observed in the spinal muscular atrophies may be accelerated (or perhaps brought about) by a malfunction in this trophic support system. We show how this model would explain the perinatal or infantile onset of the disease, the variability of the rate of evolution between the different SMA forms, and the fact that motoneuron loss is much more dramatic in SMA than in even advanced cases of myopathy. We raise the possibility that the genetic lesion that leads to the spinal muscular atrophies may directly involve the growth factor system. Preliminary results obtained in vitro using cultures of embryonic chick spinal neurons do indeed suggest that muscle of SMA patients contains substances that inhibit muscle-derived growth-promoting activities. However, such phenomena must be interpreted with caution until the neurons and molecules involved are better characterized.

Humans↗
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↗