X-linked Spinal Muscular Atrophy Research Articles

Recurrent Mutations of the Active Adenylation Domain of UBA1 in Atypical Form of VEXAS Syndrome.

Recurrent Mutations of the Active Adenylation Domain of UBA1 in Atypical Form of VEXAS Syndrome.

Fatal congenital copper transport defect caused by a homozygous likely pathogenic variant of SLC31A1.

Known hereditary human diseases featuring impaired copper trafficking across cellular membranes involve ATP7A (Menkes disease, occipital horn disease, X-linked spinal muscular atrophy type 3) and ATP7B (Wilson disease). Herein, we report a newborn infant of consanguineous parents with a homozygous pathogenic variant in a highly conserved sequence of SLC31A1, coding for the copper influx transporter 1, CTR1. This missense variant, c.236T > C, was detected by whole exome sequencing. The infant was born with pulmonary hypoplasia and suffered from severe respiratory distress immediately after birth, necessitating aggressive mechanical ventilation. At 2 weeks of age, multifocal brain hemorrhages were diagnosed by cerebral ultrasound and magnetic resonance imaging, together with increased tortuosity of cerebral arteries. Ensuing seizures were only partly controlled by antiepileptic drugs, and the infant became progressively comatose. Laboratory investigations revealed very low serum concentrations of copper and ceruloplasmin. No hair shaft abnormalities were detected by dermatoscopy or light microscopic analyses of embedded hair shafts obtained at 4 weeks of life. The infant died after redirection of care and elective cessation of invasive mechanical ventilation at 1 month of age. This case adds SLC31A1 to the genes implicated in severe hereditary disorders of copper transport in humans.

Identification of UBA1 as the causative gene of an X-linked non-Kennedy spinal-bulbar muscular atrophy.

Spinal-bulbar muscular atrophy (SBMA) (Kennedy's disease) is a motor neuron disease. Kennedy's disease is nearly exclusively caused by mutations in the androgen receptor encoding gene (AR). The results of studies aimed at identification of the genetic cause of a disease that best approximates SBMA in a pedigree (four patients) without mutations in AR are reported. Clinical investigations included thorough neurological and non-neurological examinations and testing. Genetic analysis was performed by exome sequencing using standard protocols. UBA1 mutations were modeled on the crystal structure of UBA1. The clinical features of the patients are described in detail. A missense mutation in UBA1 (c.T1499C; p.Ile500Thr) was identified as the probable cause of the non-Kennedy SBMA in the pedigree. Like AR, UBA1 is positioned on chromosome X. UBA1 is a highly conserved gene. It encodes ubiquitin-like modifier activating enzyme 1 (UBA1) which is the major E1 enzyme of the ubiquitin-proteasome system. Interestingly, UBA1 mutations can also cause infantile-onset X-linked spinal muscular atrophy (XL-SMA). The mutation identified here and the XL-SMA causative mutations were shown to affect amino acids positioned in the vicinity of UBA1's ATP binding site and to cause structural changes. UBA1 was identified as a novel SBMA causative gene. The gene affects protein homeostasis which is one of most important components of the pathology of neurodegeneration. The contribution of this same gene to the etiology of XL-SMA is discussed.

Exome sequencing can misread high variant allele fraction of somatic variants in UBA1 as hemizygous in VEXAS syndrome: a case report

BackgroundVEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome) is a recently described syndrome caused by a somatic missense variant at the methionine-41 (p.(Met41)) position in the ubiquitin-like modifier activating enzyme 1 (UBA1) in Xp11.3. Germline pathogenic variants in UBA1 are associated with a distinct phenotype: a syndrome with severe neurologic features associated with loss of anterior horn cells and infantile death denominated X-Linked Spinal Muscular Atrophy 2 (SMAX2) (OMIM 301,830).Case presentationWe report a male individual with the phenotype of VEXAS syndrome that was initially identified through exome sequencing (ES) as having a hemizygous germline variant in UBA1 due to high variant allele frequency (VAF). Research Sanger sequencing was able to confirm the absence of the p.(Met41Val) variant in a skin biopsy and in gastric mucosa tissue sample confirming the variant happened as a postzygotic event.ConclusionsThe present case exemplifies the diagnostic challenge that was imposed by the high VAF detected by ES that failed to correctly demonstrate that the variant was in a mosaic state. Sequencing of different tissues should be considered when there is conflict between the UBA1 variant status and the clinical findings.

Cellular and molecular mechanisms underlying UBA1‐mediated motor neuron degeneration in spinal muscular atrophy

Background Spinal muscular atrophy (SMA) is a neurodegenerative genetic disease caused by a homozygous deletion of the Survival Motor Neuron 1 gene (SMN1). It is characterized by the degeneration of α lower motor neurons in the anterior horn of the spinal cord, which leads to muscular atrophy. There is currently no effective therapy. Nevertheless, studies targeting ubiquitin-like modifier-activating enzyme 1 (UBA1) pathways on animal models have shown improvements in neuromuscular phenotype. Experiments have shown that there is a reduction of UBA1 in SMA and that mutations in UBA1 can cause X-linked SMA. However, the mechanism by which UBA1 mediates degeneration in SMA is unclear. Objectives & Aims Previous work was performed in the laboratory in order to identify UBA1-dependent pathways by label-free proteomics of HEK-293 cells after knockdown or overexpression of UBA1. With this pathway, specific proteins can be deregulated in SMA. Thus, this project focuses on the downstream targets of UBA1 and how UBA1 is involved. The project aims to investigate UBA1 as a mediator of neuropathological changes in SMA by studying the UBA1 distribution in post mitotic cells such as primary cultured motor neurons, and SMA cultured motor neurons as well as to identify whether UBA1 distribution is disrupted in cell models of SMA. Methodology This project investigated the role of UBA1 in SMA and, more specifically, the relevance of sub-cellular UBA1 distribution in SMA. UBA1 distribution in post-mitotic cells, including cultured primary neurons, was studied to identify whether UBA1 distribution is disrupted in cell models of SMA. UBA1 distribution was also studied in human embryonic kidney cells to confirm the distribution in dividing cells. Results This study confirmed that a change in the distribution of UBA1 was seen in cultured motor neurons over time (Fig. 1). Moreover, there was a pronounced UBA1 reduction in the nucleus in SMA motor neurons in comparison to healthy motor neurons (Fig. 2). Conclusion This research project studied the role of UBA1 distribution and its relevance to SMA. Results have produced a better understanding of UBA1 distribution in post-mitotic cells, such as cultured motor neurons and SMA motor neurons. Results suggest that understanding UBA1 distribution in SMA will be essential to future studies in reaching a therapeutic cure. Future work will include looking at the downstream effect of this change in UBA1 distribution.

A Pathogenic Missense Variant (c.1617G>A, p.Met539Ile) in UBA1 Causing Infantile X-Linked Spinal Muscular Atrophy (SMAX2)

Background: Infantile X-linked spinal muscular atrophy (SMAX2) is a rare type of spinal muscular atrophy associated with UBA1 variants.Methods: Clinical imaging and neurophysiological tests were performed on a Chinese patient with SMAX2. Further, focused panel sequencing of UBA1 was carried out on samples of both the proband and his maternal relatives.Results: The proband, a 4-year-old boy with the SMAX2 phenotype, suffered from reduced exercise capacity since infancy. His other symptoms included speech difficulties, severe nasal tone, reduced distal muscle strength, areflexia, and inadequate sucking ability. The brain MRI of the proband's showed normal results but the electromyography results showed multiple peripheral neurogenic lesions. Five male members of the proband's family were affected with the SMAX2 phenotype. They presented similar symptoms and had experienced a long and autonomous life. Molecular analysis revealed a novel missense variant (c.1617G>A, p.Met539Ile) in the exon 15 of UBA1. The proband's mother, as well as grandmother, carried the heterozygous missense UBA1 variant; whereas, the male patients from the family carried the hemizygotic variant.Conclusions: The affected members in this Chinese family showed unique features such as extended life span, no fractures, and cramps as compared with previously reported SMAX2 cases. The novel missense variant (c.1617G>A (p.Met539Ile) in UBA1 highlights the critical role of this gene in causing SMAX2 phenotype.

Functional characterizations of rare UBA1 variants in X-linked Spinal Muscular Atrophy

Background: X-linked spinal muscular atrophy (XL-SMA) results from mutations in the Ubiquitin-Like Modifier Activating Enzyme 1 ( UBA1). Previously, four novel closely clustered mutations have been shown to cause this fatal infantile disorder affecting only males. These mutations, three missense and one synonymous, all lie within Exon15 of the UBA1 gene, which contains the active adenylation domain (AAD). Methods: In this study, our group characterized the three known missense variants in vitro. Using a novel Uba1 assay and other methods, we investigated Uba1 adenylation, thioester, and transthioesterification reactions in vitro to determine possible biochemical effects of the missense variants. Results: Our data revealed that only one of the three XL-SMA missense variants impairs the Ubiquitin-adenylating ability of Uba1. Additionally, these missense variants retained Ubiquitin thioester bond formation and transthioesterification rates equal to that found in the wild type. Conclusions: Our results demonstrate a surprising shift from the likelihood of these XL-SMA mutations playing a damaging role in Uba1’s enzymatic activity with Ubiquitin, to other roles such as altering UBA1 mRNA splicing via the disruption of splicing factor binding sites, similar to a mechanism in traditional SMA, or disrupting binding to other important in vivo binding partners. These findings help to narrow the search for the areas of possible dysfunction in the Ubiquitin-proteasome pathway that ultimately result in XL-SMA. Moreover, this investigation provides additional critical understanding of the mutations’ biochemical mechanisms, vital for the development of future effective diagnostic assays and therapeutics.

Functional characterizations of rare UBA1 variants in X-linked Spinal Muscular Atrophy.

Background: X-linked spinal muscular atrophy (XL-SMA) results from mutations in the Ubiquitin-Like Modifier Activating Enzyme 1 ( UBA1). Previously, four novel closely clustered mutations have been shown to cause this fatal infantile disorder affecting only males. These mutations, three missense and one synonymous, all lie within Exon15 of the UBA1 gene, which contains the active adenylation domain (AAD). Methods: In this study, our group characterized the three known missense variants in vitro. Using a novel Uba1 assay and other methods, we investigated Uba1 adenylation, thioester, and transthioesterification reactions in vitro to determine possible biochemical effects of the missense variants. Results: Our data revealed that only one of the three XL-SMA missense variants impairs the Ubiquitin-adenylating ability of Uba1. Additionally, these missense variants retained Ubiquitin thioester bond formation and transthioesterification rates equal to that found in the wild type. Conclusions: Our results demonstrate a surprising shift from the likelihood of these XL-SMA mutations playing a damaging role in Uba1's enzymatic activity with Ubiquitin, to other roles such as altering UBA1mRNA splicing via the disruption of splicing factor binding sites, similar to a mechanism in traditional SMA, or disrupting binding to other important in vivo binding partners. These findings help to narrow the search for the areas of possible dysfunction in the Ubiquitin-proteasome pathway that ultimately result in XL-SMA. Moreover, this investigation provides additional critical understanding of the mutations' biochemical mechanisms, vital for the development of future effective diagnostic assays and therapeutics.

X-linked spinal muscular atrophy caused by de novo c.1731C>T substitution in the UBA1 gene

Infantile X-linked spinal muscular atrophy (SMAX2) is a rare form of spinal muscular atrophy manifesting as severe hypotonia, areflexia, arthrogryposis, facial weakness and cryptorchidism, and frequently accompanied by bone fractures. We present a male patient with SMAX2 who presented with typical symptoms at birth, preceded by reduced fetal movements in the second and third trimesters of pregnancy. Clinical examination revealed a myopathic face with a characteristic tent-shaped open mouth, tongue fibrillations, profound muscle weakness, areflexia, multiple contractures, mild skeletal abnormalities and cryptorchidism. In the first days of the patient’s life, fractures of the right femur and right humerus were found; however, calcium–phosphate metabolism and densitometric examination were normal. Molecular analysis revealed a de novo c.1731C>T substitution in the UBA1 gene, which was localized in exon 15, the specific hot spot for mutation. © 2015 Elsevier B.V. All rights reserved.

X-linked spinal muscular atrophy in mice caused by autonomous loss of ATP7A in the motor neuron.

ATP7A is a copper-transporting P-type ATPase that is essential for cellular copper homeostasis. Loss-of-function mutations in the ATP7A gene result in Menkes disease, a fatal neurodegenerative disorder resulting in seizures, hypotonia and failure to thrive, due to systemic copper deficiency. Most recently, rare missense mutations in ATP7A that do not impact systemic copper homeostasis have been shown to cause X-linked spinal muscular atrophy type 3 (SMAX3), a distal hereditary motor neuropathy. An understanding of the mechanistic and pathophysiological basis of SMAX3 is currently lacking, in part because the disease-causing mutations have been shown to confer both loss- and gain-of-function properties to ATP7A, and because there is currently no animal model of the disease. In this study, the Atp7a gene was specifically deleted in the motor neurons of mice, resulting in a degenerative phenotype consistent with the clinical features in affected patients with SMAX3, including the progressive deterioration of gait, age-dependent muscle atrophy, denervation of neuromuscular junctions and a loss of motor neuron cell bodies. Taken together, these data reveal autonomous requirements for ATP7A that reveal essential roles for copper in the maintenance and function of the motor neuron, and suggest that SMAX3 is caused by a loss of ATP7A function that specifically impacts the spinal motor neuron.

Yeast Augmented Network Analysis (YANA): a new systems approach to identify therapeutic targets for human genetic diseases

Genetic interaction networks that underlie most human diseases are highly complex and poorly defined. Better-defined networks will allow identification of a greater number of therapeutic targets.Here we introduce our Yeast Augmented Network Analysis (YANA) approach and test it with the X-linked spinal muscular atrophy (SMA) disease gene UBA1. First, we express UBA1 and a mutant variant in fission yeast and use high-throughput methods to identify fission yeast genetic modifiers of UBA1. Second, we analyze available protein-protein interaction network databases in both fission yeast and human to construct UBA1 genetic networks. Third, from these networks we identified potential therapeutic targets for SMA. Finally, we validate one of these targets in a vertebrate (zebrafish) SMA model. This study demonstrates the power of combining synthetic and chemical genetics with a simple model system to identify human disease gene networks that can be exploited for treating human diseases.

Yeast Augmented Network Analysis (YANA): a new systems approach to identify therapeutic targets for human genetic diseases.

Genetic interaction networks that underlie most human diseases are highly complex and poorly defined. Better-defined networks will allow identification of a greater number of therapeutic targets. Here we introduce our Yeast Augmented Network Analysis (YANA) approach and test it with the X-linked spinal muscular atrophy (SMA) disease gene UBA1.First, we express UBA1 and a mutant variant in fission yeast and use high-throughput methods to identify fission yeast genetic modifiers of UBA1. Second, we analyze available protein-protein interaction network databases in both fission yeast and human to construct UBA1 genetic networks. Third, from these networks we identified potential therapeutic targets for SMA. Finally, we validate one of these targets in a vertebrate (zebrafish) SMA model. This study demonstrates the power of combining synthetic and chemical genetics with a simple model system to identify human disease gene networks that can be exploited for treating human diseases.

Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene

Infantile-onset X-linked spinal muscular atrophy (SMAX2) is a rare lethal disorder linked to mutations in the UBA1 (previously UBE1) gene, encoding ubiquitin-activating enzyme 1 that has an important role in the ubiquitin-proteasome pathway. Published pathological reports are scarce. Here we report a male infant who presented from birth with predominantly truncal hypotonia following an antenatal history of reduced fetal movements. He had a myopathic face, profound weakness, multiple contractures and areflexia. Creatine kinase was moderately raised. Brain MRI showed non-specific symmetrical periventricular white matter changes. Neurophysiology revealed evidence of motor and sensory involvement and muscle biopsy showed marked inflammatory changes with subtle features suggestive of acute denervation. UBA1 sequencing revealed a novel hemizygous missense mutation (c.1670A>T; p.Glu557Val). He died from progressive respiratory failure at 4 months. On post mortem assessment, in addition to severe ventral motor neuron pathology, there was widespread involvement of the sensory system, as well as developmental and degenerative cerebellar abnormalities. In contrast to typical SMN1-associated SMA, the thalamus was unaffected. These findings indicate that SMAX2 is more accurately classified as a motor sensory neuronopathy rather than a pure anterior horn cell disorder. Ubiquitin-proteasome pathway defects may not only cause neurodegeneration but also affect normal neuronal development.

Conditional Knockout of the Menkes Disease Copper Transporter Demonstrates Its Critical Role in Embryogenesis

The transition metal, copper (Cu), is an enzymatic cofactor required for a wide range of biochemical processes. Its essentiality is demonstrated by Menkes disease, an X-linked copper deficiency disorder characterized by defects in nervous-, cardiovascular- and skeletal systems, and is caused by mutations in the ATP7A copper transporter. Certain ATP7A mutations also cause X-linked Spinal Muscular Atrophy type 3 (SMAX3), which is characterized by neuromuscular defects absent an underlying systemic copper deficiency. While an understanding of these ATP7A-related disorders would clearly benefit from an animal model that permits tissue-specific deletion of the ATP7A gene, no such model currently exists. In this study, we generated a floxed mouse model allowing the conditional deletion of the Atp7a gene using Cre recombinase. Global deletion of Atp7a resulted in morphological and vascular defects in hemizygous male embryos and death in utero. Heterozygous deletion in females resulted in a 50% reduction in live births and a high postnatal lethality. These studies demonstrate the essential role of the Atp7a gene in mouse embryonic development and establish a powerful model for understanding the tissue-specific roles of ATP7A in copper metabolism and disease.

Rare Missense and Synonymous Variants in UBE1 Are Associated with X-Linked Infantile Spinal Muscular Atrophy

X-linked infantile spinal muscular atrophy (XL-SMA) is an X-linked disorder presenting with the clinical features hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and infantile death. To identify the XL-SMA disease gene, we performed large-scale mutation analysis in genes located between markers DXS8080 and DXS7132 (Xp11.3-Xq11.1). This resulted in detection of three rare novel variants in exon 15 of UBE1 that segregate with disease: two missense mutations (c.1617 G-->T, p.Met539Ile; c.1639 A-->G, p.Ser547Gly) present each in one XL-SMA family, and one synonymous C-->T substitution (c.1731 C-->T, p.Asn577Asn) identified in another three unrelated families. Absence of the missense mutations was demonstrated for 3550 and absence of the synonymous mutation was shown in 7914 control X chromosomes; therefore, these results yielded statistical significant evidence for the association of the synonymous substitution and the two missense mutations with XL-SMA (p = 2.416 x 10(-10), p = 0.001815). We also demonstrated that the synonymous C-->T substitution leads to significant reduction of UBE1 expression and alters the methylation pattern of exon 15, implying a plausible role of this DNA element in developmental UBE1 expression in humans. Our observations indicate first that XL-SMA is part of a growing list of neurodegenerative disorders associated with defects in the ubiquitin-proteasome pathway and second that synonymous C-->T transitions might have the potential to affect gene expression.

Severe lethal spinal muscular atrophy variant with arthrogryposis

Spinal muscular atrophies are a clinically and genetically heterogeneous group of disorders. Atypical forms of the disease have also been described, including those with associated sensory deficits, hearing loss, cerebellar hypoplasia, congenital heart defects, arthrogryposis, and bone fractures at birth. The patient described here is a male infant, born to a 30-year-old mother at 34 weeks of gestation complicated with polyhydramnios. The first son of consanguineous parents had died with the same clinical features. The patient required ventilatory support because of respiratory failure after the birth and died on day 13. His physical examination revealed profound generalized hypotonia, absence of deep tendon and neonatal reflexes, dysmorphic facies, arthrogryposis, clinodactyly, and left femur fracture. A muscle biopsy revealed variation in fiber size with occasional hypertrophic fibers. The postmortem examination revealed loss and degeneration of anterior horn cells. We propose that the patient, who presented with severe hypotonia, femur fracture, arthrogryposis, dysmorphic features, history of early death of his brother with the same clinical features and parental consanguinity, had probable X-linked spinal muscular atrophy. However, autosomal-recessive inheritance can not be completely excluded.

93rd ENMC international workshop: non-5q-spinal muscular atrophies (SMA) – clinical picture (6–8 April 2001, Naarden, The Netherlands)

This 93rd SMA workshop followed the European Neuromuscular Centre (ENMC) tradition to combine clinical and molecular topics with the aim of not only exchanging current knowledge but also initiating collaborative studies. Despite important milestones in research on autosomal recessive SMA with localisation on chromosome 5q (SMA 5q) in the past 10 years, we are just beginning to understand the molecular basis and phenotypic spectrum of non-5q-SMA entities. The possibility of analysing the SMN gene allowed the delineation of the diagnostic criteria of ‘classical’ proximal SMA and its clinical variability. On the other hand, different entities of SMA could be defined that show atypical features and proved to be unlinked to chromosome 5q. The field of interest has therefore been focussed on further genes responsible for anterior horn cell loss. This will contribute to further understand the underlying pathogenetic pathways, the complex protein interactions and genotype–phenotype correlations in various types of motor neuron disorders. The workshop was structured in a first part, briefly reviewing the current status of SMA 5q including animal models which have been generated. The second part included different sessions on non-5q-SMA forms; clinical and diagnostic criteria were discussed and adapted to current knowledge. These were summarized by invited chairpersons (named in brackets) and followed by contributions of the participants. The following short summaries cover the essentials of the reviews, the discussion and the consensus achieved. 1. Update on SMA 5q

Recent progress in identification of the X-linked Spinal Muscular Atrophy (XLSMA) gene confirms a major disease locus between Xpl 1.3-Xpl 1.2

We report our recent efforts toward the identification of the X-linked lethal infantile spinal muscular atrophy (XL-SMA) locus. Our collaborative group has previously described several families which display an X-linked recessive form of human motor neuron disease (AJHG. 61S. # 1554, 1997) Defining features include multiple generations of males with congenital onset of severe hypotonia, contracturcs and fractures; muscle biopsy indicative of neurogcnic atrophy; and autopsy indicating loss of anterior horn cells. The first family analyzed for linkage mapped to Xp 11.3-q11 2, and multipoint analysis refined this interval to a 11 cM region defined by DXS993-DXS991, with a maximum LOD score of 2.63 (Hum Molec Genet, 4(7): 1213-16,1995). Subsequently, seven unrelated families (six N. American, one European) have been identified and ascertained. These families were selected based on the above described inclusion criteria. Genomic DNA was prepared from blood and/or tissue specimens from affected and unaffected males, and obligate earner females, and analyzed using X-chromosome highly polymorphic DNA repeats Concordance analysis was used to define maternal meiotic recombination breakpoints surrounding a disease gene region, followed by multipoint linkage analysis using additional DNA markers. Results of these studies were interpreted using the LINKAGE and VITESSE programs, using the assumptions of a completely penetrant disease, with a gene frequency of 1 × 10−6. These combined results indicated that in addition to the first family reported above, four additional families have been linked to the same candidate disease gene interval, Xp11.3-q11 2. Multipoint linkage analysis has been completed for three of these four families and has refined this interval to a region defined by DXS991-DXS1003, with a maximum LOD score of 2.73 for these three families. The total additive LOD score for these three families, and the family previously published, is 5.36 at a Theta of 0.00 These results strongly support the existence of a major disease locus for XL-SMA between DXS 1003-DXS 991 (Xp 11.3-Xp 11.21) We are attempting to narrow the disease gene region through a search for recombinant individuals in each of the families using additional polymorphic markers We are also focusing our efforts on mutation screening of candidate disease genes within this region, particularly new candidates identified from a recently completed 1 1 mB transcript map of Xp11.3 Latest findings will be presented.

Serum cholinesterase activity in infantile and juvenile spinal muscular atrophy.

Serum acetylcholinesterase (AChE) and pseudocholinesterase (ChE) activity in infantile and juvenile spinal muscular atrophy (SMA) was determined. The total AChE activity was either normal or decreased in the childhood SMA (Type 1), the other SMA groups and disease controls (ALS, X-linked SMA). In the majority of SMA Type 1 cases (6/7 tested) an absence of the asymmetric A12 form was found. This was accompanied by changes in the other asymmetric and globular forms. The latter was, however, not specific for SMA Type 1 cases. The ChE activity was increased in the majority of SMA cases as well as disease controls. The asymmetric A12 ChE form was increased in all SMA Type 3 cases, the values of this form in SMA Type 1 was variable. A change in the ChE globular forms in SMA Type 1 and SMA Type 2 was a frequent finding. It is suggested that the absence of the asymmetric A12 AChE form in SMA Type 1 arises because of muscle cell immaturity and undeveloped muscle-nerve interactions. The reason of ChE changes is obscure.

Localization of the gene for X-linked spinal muscular atrophy.

We used probes for DNA polymorphisms on the X chromosome to study genetic linkage in seven families with X-linked adult-onset spinal muscular atrophy. We found significant linkage to the marker DXYS1 on the proximal X chromosome long arm and loose linkage or nonlinkage to markers elsewhere. Our analysis localizes the gene defect for this form of anterior horn cell disease.