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PubMed1992

Intrafamilial heterogeneity in hereditary motor neuron disease.

Although there are varied inheritance patterns in motor neuron disease (MND), the phenotype of MND is reported to be constant within these families, ie, cases of amyotrophic lateral sclerosis or primary lateral sclerosis do not occur in pedigrees with cases of spinal muscular atrophy. We describe four pedigrees whose members diverged in the phenotype of MND expressed. The intrafamilial variation of phenotype suggests a similar pathogenesis for some of the varied types of familial MND and the need for careful inquiry of family history in all patients with MND.

Aged↗
PubMed2003

Protein phosphatase 4 interacts with the Survival of Motor Neurons complex and enhances the temporal localisation of snRNPs.

Protein phosphatase 4 (PPP4) is a ubiquitous essential protein serine/threonine phosphatase found in higher eukaryotes. Coordinate variation of the levels of the catalytic subunit (PPP4c) and the regulatory subunit (R2) suggests that PPP4c and R2 form a heterodimeric core to which other regulatory subunits bind. Two proteins that specifically co-purify with Flag-epitope-tagged R2 expressed in HEK-293 cells were identified as Gemin3 and Gemin4. These two proteins have been identified previously as components of the Survival of Motor Neurons (SMN) protein complex, which is functionally defective in the hereditary disorder spinal muscular atrophy. Immuno-sedimentation of the epitope-tagged SMN protein complex from HeLa cells expressing CFP-SMN showed that the SMN protein interacts, as previously reported, with Gemin2 (SIP1), Gemin3 and Gemin4 and in addition associates with PPP4c. The SMN complex has been implicated in the assembly and maturation of small nuclear ribonucleoproteins (snRNPs). Expression of GFP-R2-PPP4c in HeLa cells enhances the temporal localisation of newly formed snRNPs, which is consistent with an association of R2-PPP4c with the SMN protein complex.

Blotting, Northern↗
PubMed2003

Calpainopathy: how broad is the spectrum of clinical variability?

Five affected siblings were referred with a probable diagnosis of proximal adult-type spinal muscular atrophy (SMA) based on lower motor neuron signs (muscle weakness and atrophy, hypotony, hypoactive or absent reflexes, and fasciculations), normal or borderline serum creatine kinase levels, and a neurogenic pattern on electromyography, compatible with motor neuron disease, in one patient. No exon 7-8 deletion in the survival motor neuron (SMN) gene was found. Linkage analysis excluded the SMN and all known autosomal recessive limb girdle muscular dystrophy loci, with the exception of LGMD-2A. A homozygous R769Q mutation in the calpain-3 gene and absence of muscle calpain-3 protein confirmed a calpainopathy. This family suggests that the clinical spectrum of calpainopathy might be broader and that this diagnosis might be considered in patients with an atypical motor neuron disease.

Adult↗
PubMed2000

Motor neuron diseases in the university hospital of Fortaleza (Northeastern Brazil): a clinico-demographic analysis of 87 cases.

In this retrospective (1980-1998) study, we have analyzed clinico-demographically, from the records of the University Hospital of Fortaleza (Brazil), a group of 87 patients showing signs and symptoms of motor neuron diseases (MNDs). Their diagnosis was determined clinically and laboratorially. The WFN criteria were used for amyotrophic lateral sclerosis (ALS) diagnosis. The clinico-demographic analysis of the 87 cases of MNDs showed that 4 were diagnosed as spinal muscular atrophy (SMA), 5 cases as ALS subsets: 2 as progressive bulbar paralysis (PBP), 2 as progressive muscular atrophy (PMA) and 1 as monomelic amyotrophy (MA), and 78 cases of ALS. The latter comprised 51 males and 27 females, with a mean age of 42.02 years. They were sub-divided into 4 groups according to age: from 15 to 29 years (n= 17), 30 to 39 years (n= 18), 40 to 69 years (n= 39) and 70 to 78 years (n= 4). From the 78 ALS patients, 76 were of the classic sporadic form whilst only 2 were of the familial form. The analysis of the 87 patients with MNDs from the University Hospital of Fortaleza showed a predominance of ALS patients, with a high number of cases of juvenile and early onset adult sporadic ALS.

Adolescent↗
PubMedDate not supplied

Canine motor neuron disease: clinicopathologic features and selected indicators of oxidative stress.

Hereditary canine spinal muscular atrophy (HCSMA) is an inherited motor neuron disease affecting a kindred of Brittanies. We have examined the clinicopathologic abnormalities in 57 animals with HCSMA, including 43 affected adult dogs and 14 homozygote pups. We also measured selected biochemical indices of oxidative stress: serum vitamin E (alpha-tocopherol) and Se concentrations; serum concentrations of Cu, Zn, Mg, and Fe; and total superoxide dismutase and glutathione peroxidase activities in red blood cells. Dogs with HCSMA had the following abnormalities: regenerative anemia, hypoglobulinemia, hypochloremia, and abnormally high creatine kinase and liver alkaline phosphatase activities. Serum Cu concentration was significantly (P = .01) increased in adult dogs with HCSMA compared to control dogs. Serum vitamin E concentrations tended to be lower in adult dogs with HCSMA compared to controls, and were significantly (P = .01) lower in homozygote pups compared to control pups.

Animals↗
PubMed1990

Transient cytoplasmic bodies in muscle of three infants with Werdnig-Hoffmann disease.

We present three instances in which cytoplasmic bodies in muscle fibers were associated with Werdnig-Hoffmann disease. The children presented within the first 6 weeks of life with clinical symptoms and laboratory studies indicative of infantile spinomuscular atrophy (ISMA). Initial muscle biopsies in each case revealed signs of muscle immaturity and cytoplasmic bodies but lacked features of denervation. Follow-up biopsies in 2 cases revealed changes typical of ISMA, but cytoplasmic bodies were no longer present. A follow-up biopsy was not available in the third child who also had a clinical course consistent with ISMA. We discuss the pathogenesis of cytoplasmic bodies and their significance in association with Werdnig-Hoffmann disease.

Biopsy↗
PubMed2004

Quantitative analysis of SMN1 gene and estimation of SMN1 deletion carrier frequency in Korean population based on real-time PCR.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder, caused by homozygous absence of the survival motor neuron gene (SMN1) in approximately 94% of patients. Since most carriers have only one SMN1 gene copy, several SMN1 quantitative analyses have been used for the SMA carrier detection. We developed a reliable quantitative real-time PCR with SYBR Green I dye and studied 13 patients with SMA and their 24 parents, as well as 326 healthy normal individuals. The copy number of the SMN1 gene was determined by the comparative threshold cycle (Ct) method and albumin was used as a reference gene. The homozygous SMN1 deletion ratio of patients was 0.00 and the hemizygous SMN1 deletion ratio of parents ranged from 0.39 to 0.59. The deltadelta Ct ratios of 7 persons among 326 normal individuals were within the carrier range, 0.41-0.57. According to these data, we estimated the carrier and disease prevalence of SMA at 1/47 and 1/8,496 in Korean population, respectively. These data indicated that there would be no much difference in disease prevalence of SMA compared with western countries. Since the prevalence of SMA is higher than other autosomal recessive disorders, the carrier detection method using real-time PCR could be a useful tool for genetic counseling.

Adult↗
PubMed2000

The neuronal apoptosis inhibitory protein (Naip) is expressed in macrophages and is modulated after phagocytosis and during intracellular infection with Legionella pneumophila.

Legionella pneumophila is an intracellular pathogen that causes Legionnaires' disease in humans. Inbred mouse strains are uniformly resistant to L. pneumophila infection with the notable exception of A/J, where the chromosome 13 locus Lgn1 renders A/J macrophages permissive to L. pneumophila replication. The mouse Lgn1 region is syntenic with the spinal muscular atrophy (SMA) locus on human chromosome 5 and includes several copies of the neuronal apoptosis inhibitory protein (Naip) gene. We have analyzed a possible link among Lgn1, Naip, and macrophage function. RNA expression studies show that Naip (mostly copy 2) mRNA transcripts are expressed in macrophage-rich tissues, such as spleen, lung, and liver and are abundant in primary macrophages. Immunoblotting and immunoprecipitation analyses identify Naip protein expression in mouse macrophages and in macrophage cell lines RAW 264.7 and J774A. Interestingly, macrophages from permissive A/J mice express significantly less Naip protein than their nonpermissive C57BL/6J counterpart. Naip protein expression is increased after phagocytic events. Naip protein levels during infection with either virulent or avirulent strains of L. pneumophila increase during the first 6 h postinfection and remain elevated during the 48-h observation period. This enhanced expression is also observed in macrophages infected with Salmonella typhimurium. Likewise, an increase in Naip protein levels in macrophages is observed 24 h after phagocytosis of Latex beads. The cosegregation of Lgn1 and Naip together with the detected Naip protein expression in host macrophages as well as its modulation after phagocytic events and during intracellular infection make it an attractive candidate for the Lgn1 locus.

Animals↗
PubMed1998

[Genetic diagnosis of IVF embryos: preliminary results from 'preimplantation genetic diagnoses' in the Netherlands].

Preimplantation genetic diagnosis (PGD) is a very early form of genetic testing. It involves testing one or two cells taken from a recent embryo of eight cells produced by in vitro fertilization, and selective transfer of genetically normal embryos. So far in the Academic Hospital Maastricht, the Netherlands, 20 couples have undergone PGD, resulting in 6 ongoing pregnancies (one twin pregnancy). In three women the indications for PGD were: cystic fibrosis, sex-linked Pelizaeus-Merzbacher disease and chromosomal translocation, respectively. In the Netherlands PGD is only allowed if there is a high risk of a serious genetic disease. PGD can be carried out in Maastricht for: cystic fibrosis, sex-linked diseases, chromosomal abnormalities, fragile X syndrome, spinal muscular atrophy and myotonic dystrophy. The advantage of PGD is that it excludes the necessity of a therapeutic abortion. Disadvantages ages are the requirement of in vitro fertilization, which has only a 15-20% pregnancy rate, and the experimental nature of the PGD procedure. To date, about 200 children have been born worldwide following PGD.

Adult↗
PubMed1999

[Thoughts on the illness of Hermann von Reichenau (1019-1054)].

Hermann from Reichenau--Hermannus contractus--apparently suffered from a disease which led to considerable physical handicap leaving his outstanding intellectual talents undamaged. Various statements about his condition--an epileptic, suffering from spasticity, afflicted by poliomyelits--have never been reconsidered. Using the biography written by this disciple Berthold, the most important contemporary source about Hermanns' life, an approach to a correct diagnosis from a neurologists point of view was the aim of this study. By unbiased analysis of the symptoms described by Berthold a neurologic syndrome is worked out: it comprised a flaccid tetraparesis involving the bulbar area. The sensory as well as the autonomic nervous system were apparently not involved. Intellectual functions were unaffected. Considering this syndrome and other details of Hermanns' life as well as the beginning and course of his illness, a traumatic birth injury, an early childhood disease and a central nervous as well as an infectious disease are ruled out. Muscle disease is considered possible, but motor neuron disease--either amyotrophic lateral sclerosis or spinal muscular atrophy--seems to be the most convincing diagnosis.

Famous Persons↗
PubMed2000

Functional motor unit failure precedes neuromuscular degeneration in canine motor neuron disease.

Hereditary canine spinal muscular atrophy (HCSMA) features rapidly progressive muscle weakness that affects muscles in an apparent proximal-to-distal gradient. In the medial gastrocnemius (MG) muscle of homozygous HCSMA animals, motor unit tetanic failure is apparent before the appearance of muscle weakness and appears to be presynaptic in origin. We determined whether structural changes in neuromuscular junctions or muscle fibers were apparent at times when tetanic failure is prevalent. We were surprised to observe that, at ages when motor unit tetanic failure is common, the structure of neuromuscular junctions and the appearance of muscle fibers in the MG muscle were indistinguishable from those of symptom-free animals. In contrast, in more proximal muscles, many neuromuscular junctions were disassembled, with some postsynaptic specializations only partially occupied by motor nerve terminals, and muscle fiber atrophy and degeneration were also apparent. These observations suggest that the motor unit tetanic failure observed in the MG muscle in homozygous animals is not due to synaptic degeneration or to pathological processes that affect muscle fibers directly. Together with previous physiological analyses, our results suggest that motor unit failure is due to failure of neuromuscular synaptic transmission that precedes nerve or muscle degeneration.

Animals↗
PubMedDate not supplied

The reorganisation of motor units in different motor neuron disorders.

A study was made of the degree and sequence of neurophysiological changes during motor unit reorganisation in motor neuron disease (MND), spinal muscular atrophy (SMA), and prior polio. Concentric needle EMG was used in conjunction with our own computerized EMG-LAB system. Motor unit action potential (MUAP) parameters were measured in 543 muscles on weak and maximum effort. MUAP amplitude and area were found to increase in the early stages of damage, declining to normal or subnormal values in the course of the disease. It was concluded that in MND there is a pathological sequence: denervation--reinnervation--terminal denervation. The increase in MUAP amplitude and area in the early stages of lesion, reflecting reinnervation, was much greater in SMA than MND and most marked in prior polio. The eventual decrease is an expression of terminal decompensation.

Action Potentials↗
PubMed2003

Active transport of the survival motor neuron protein and the role of exon-7 in cytoplasmic localization.

Spinal muscular atrophy (SMA) is a neurodegenerative disease caused by deletion and/or mutation of the survival motor neuron protein Gene (SMN1) that results in the expression of a truncated protein lacking the C terminal exon-7. Whereas SMN has been shown to be an important component of diverse ribonucleoprotein (RNP) complexes, its function in neurons is unknown. We hypothesize that the active transport of SMN may be important for neurite outgrowth and that disruption of exon-7 could impair its normal intracellular trafficking. SMN was localized in granules that were associated with cytoskeletal filament systems and distributed throughout neurites and growth cones. Live cell imaging of enhanced green fluorescent protein (EGFP)-SMN granules revealed rapid, bidirectional and cytoskeletal-dependent movements. Exon-7 was necessary for localization of SMN into the cytoplasm but was not sufficient for granule formation and transport. A cytoplasmic targeting signal within exon-7 was identified that could completely redistribute the nuclear protein D-box binding factor 1 into the cytoplasm. Neurons transfected with SMN lacking exon-7 had significantly shorter neurites, a defect that could be rescued by redirecting the exon-7 deletion mutant into neurites by a targeting sequence from growth-associated protein-43. These findings provide the first demonstration of cytoskeletal-based active transport of SMN in neuronal processes and the function of exon-7 in cytoplasmic localization. Such observations provide motivation to investigate possible transport defects or inefficiency of SMN associated RNPs in motor neuron axons in SMA.

Actin Cytoskeleton↗
PubMedDate not supplied

[A case of progressive bulbar paralysis in a child (Fazio-Londe disease)].

The reported case was diagnosed in a girl aged 14, in whom the first signs developed at the age of 6, with progressive involvement of the cranial nerves IX, X, XI and XII, and V with VII. After ruling out other possible causes the diagnosis of the Fazio-Londe disease was established. Electromyographic examination confirming the diagnosis demonstrated also evidence of changes of neurogenic type in the muscles of upper extremities despite absence of demonstrable clinical abnormalities, which, as suggest the authors, may support the hypothesis of the similarity of the disease to other forms of spinal muscular atrophy, such as Werdnig-Hoffman and Kugelberg-Welander diseases.

Adolescent↗