X-Linked Infantile Spinal Muscular Atrophy

Mendelian MONDO:0010532 Pathograph 27 Show in embeddings browser Motor Neuron Disease

X-linked infantile spinal muscular atrophy (XL-SMA; SMAX2; X-linked spinal muscular atrophy with arthrogryposis) is a rare UBA1-related neuromuscular disorder. Classic cases are hemizygous males with prenatal or neonatal onset of reduced fetal movement, severe hypotonia, areflexia, weakness, arthrogryposis, fractures, and progressive ventilatory failure. Most reported familial cases follow X-linked transmission through usually unaffected heterozygous females, although de novo hemizygous variants also occur. Human neuropathology confirms severe ventral/anterior-horn motor-neuron loss; one detailed autopsy also found sensory-system and cerebellar involvement, arguing that SMAX2 need not be a pure anterior-horn-cell disorder. UBA1 initiates ubiquitination, and the original synonymous allele reduces UBA1 expression, but the tissue and downstream pathway that determine selective neuromuscular injury remain unsettled. Model-organism work supports both neuronal proteostasis and muscle-autonomous contributions. SMAX2 is distinct from SMN1-related proximal SMA, AR-related Kennedy disease, ATP7A-related X-linked distal SMA type 3, and the recently described adult-onset UBA1-related non-Kennedy spinal-bulbar muscular atrophy.

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1
Inheritance
8
Pathophys.
1
Histopath.
16
Phenotypes
2
Gaps
27
Pathograph
1
Genes
8
Medical Actions
6
Differentials
4
References
👪

Inheritance

1
X-linked recessive inheritance HP:0001419
X-linked recessive inheritance
Show evidence (3 references)
PMID:20301739 SUPPORT Human Clinical
"By definition, XL-SMA is inherited in an X-linked manner."
GeneReviews establishes X-linked inheritance for XL-SMA.
PMID:20301739 SUPPORT Human Clinical
"Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and will usually not be affected."
Confirms affected males and usually-unaffected carrier females, consistent with X-linked recessive inheritance.
PMID:39762237 SUPPORT Human Clinical
"We identified a de novo hemizygous mutation, c.1660 C > T (p.Pro554Ser), in exon 15 of the UBA1 gene in this baby."
Demonstrates that an affected male may carry a de novo hemizygous UBA1 variant rather than an inherited maternal allele.
?

Discussions and Knowledge Gaps

2
Do generic UBA1 knockdown models reproduce the allele-specific human SMAX2 mechanism in motor neurons, sensory neurons, cerebellar cells, and skeletal muscle, given that p.Met539Ile and p.Ser547Gly retain adenylation activity whereas p.Glu557Val does not?
HUMAN MODEL MISMATCH OPEN gap_smax2_human_model_allele_and_tissue_mismatch
Attached to
pathophysiology#Allele-Specific UBA1 Dysfunction pathophysiology#Candidate UBA1-Dependent Cellular Dysregulation pathophysiology#Anterior Horn Motor Neuron Degeneration pathophysiology#Sensory Neuron and Tract Pathology pathophysiology#Skeletal Muscle-Autonomous Dysfunction
Muscle-targeted UBA1 knockdown in Drosophila and mice reduces ubiquitination and muscle function, but it does not model a specific human exon-15 allele. Human biochemical assays show heterogeneous effects across missense variants, and patient tissue establishes motor, sensory, and cerebellar pathology without demonstrating reduced ubiquitination. The model result is therefore evidence for a testable muscle-autonomous route, not proof of the human mechanism.
Proposed experiments
Isogenic human SMAX2 allele-by-cell-type panel
isogenic iPSC allele-by-cell-type experiment Relation: this experiment is of type this experiment type This experiment is of type isogenic iPSC allele-by-cell-type experiment.
exp_smax2_isogenic_allele_tissue_panel
Introduce p.Met539Ile, p.Ser547Gly, p.Glu557Val, and c.1731C>T separately into one human iPSC background, differentiate matched motor neurons, sensory neurons, and skeletal muscle fibers, and compare them with corrected patient-derived lines and wild-type controls.
Model systems
Isogenic human iPSC-derived motor, sensory, and skeletal-muscle models
Allele-matched human cultures tested separately and in motor-unit co-culture.
IPSC DERIVED MODEL
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
motor neuron CL:0000100 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses motor neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology. sensory neuron CL:0000101 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses sensory neuron (CL:0000101). CL:0000101 is a cell type from the Cell Ontology. skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this experimental model uses this cell type This experimental model uses skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
Readouts
Allele-specific UBA1 reaction kinetics and ubiquitin conjugation
pathophysiology#Allele-Specific UBA1 Dysfunction
Measure adenylation, thioester formation, E2 transfer, global and substrate-specific ubiquitination, and proteasome flux in each cell type.
Cell-type injury and function
pathophysiology#Candidate UBA1-Dependent Cellular Dysregulation
Measure neuronal survival and axonal integrity, neuromuscular-junction formation, muscle contractility, and transcript splicing.
Decision criterion
A human mechanism is supported only if an allele-specific molecular defect reproducibly precedes injury in the clinically implicated cell type; failure of knockdown-like ubiquitination changes in p.Met539Ile or p.Ser547Gly would refute a uniform adenylation/ubiquitination-deficiency model.
Would support
pathophysiology#Allele-Specific UBA1 Dysfunction pathophysiology#Candidate UBA1-Dependent Cellular Dysregulation
Would refute
pathophysiology#Skeletal Muscle-Autonomous Dysfunction
Genotype-resolved human SMAX2 multi-tissue profiling
genotype-resolved human multi-tissue study Relation: this experiment is of type this experiment type This experiment is of type genotype-resolved human multi-tissue study.
exp_smax2_patient_tissue_ubiquitinome
Prospectively collect fibroblasts, blood, clinically obtained muscle, and postmortem nervous tissue across severe and mild SMAX2 alleles, with matched neurologic disease and unaffected controls, and profile UBA1 isoforms, splicing, binding partners, ubiquitin conjugates, proteasome flux, and tissue pathology.
Model systems
Human SMAX2 patient tissues and primary cultures
Patient material stratified by UBA1 allele and clinical severity.
PRIMARY CELL CULTURE
human NCBITaxon:9606 NCBI Taxonomy (NCBITaxon) Relation: this experimental model is built in this organism This experimental model is built in human, annotated with Homo sapiens (NCBITaxon:9606). NCBITaxon:9606 is an organism from the NCBI Taxonomy.
Readouts
Tissue-specific UBA1 mechanism
pathophysiology#Candidate UBA1-Dependent Cellular Dysregulation
Identify whether altered splicing, binding partners, ubiquitination, or proteasome flux co-segregates with tissue injury and allele severity.
Decision criterion
Concordant allele- and tissue-specific molecular changes in human material must match the affected motor, sensory, cerebellar, or muscle compartment before an animal-knockdown mechanism is promoted to a human causal claim.
Would support
pathophysiology#Anterior Horn Motor Neuron Degeneration pathophysiology#Sensory Neuron and Tract Pathology pathophysiology#Cerebellar Developmental and Degenerative Abnormalities pathophysiology#Skeletal Muscle-Autonomous Dysfunction
Show evidence (2 references)
PMID:42402962 SUPPORT Model Organism
"However, it remains unexplored how UBA1 impacts the muscle proteome, and whether muscle weakness can arise from reducing UBA1 function solely in skeletal muscle."
States the motivating tissue-mechanism question addressed in models but not yet resolved in human SMAX2.
PMID:29034082 SUPPORT In Vitro
"Our data revealed that only one of the three XL-SMA missense variants impairs the Ubiquitin-adenylating ability of Uba1."
The allele-specific biochemical result establishes why generic UBA1 knockdown cannot be assumed to model every human SMAX2 allele.
What are genotype-specific birth prevalence, survival, and penetrance in heterozygous females, including the role of X-inactivation and de novo variants?
KNOWLEDGE GAP OPEN gap_smax2_sex_specific_ascertainment_and_prevalence
Attached to
pathophysiology#Allele-Specific UBA1 Dysfunction
Reports are dominated by severely affected hemizygous male probands and multiplex families, while GeneReviews states that heterozygous females are usually unaffected and a recent case was de novo. This design cannot provide an unbiased female penetrance estimate, sex-specific rate, or genotype-specific natural history.
Show evidence (1 reference)
PMID:20301739 SUPPORT Human Clinical
"females who inherit the pathogenic variant will be heterozygotes and will usually not be affected."
The qualifier "usually" leaves female penetrance and modifiers unresolved.
⚙

Pathophysiology

8
Allele-Specific UBA1 Dysfunction
SMAX2-associated hemizygous variants cluster in exon 15 near the active adenylation domain, but they do not share one demonstrated biochemical defect. The recurrent synonymous c.1731C>T allele reduces UBA1 expression. In vitro, p.Met539Ile and p.Ser547Gly did not show statistically reduced adenylation, whereas p.Glu557Val showed a moderate reduction. The initiating lesion is therefore modeled as allele-specific UBA1 dysfunction rather than uniform adenylation failure or complete loss of UBA1 function.
Downstream
Candidate UBA1-Dependent Cellular Dysregulation Different alleles may perturb splicing, binding partners, ubiquitin handling, or other UBA1-dependent processes through mechanisms not yet established in patient tissue.
Show evidence (5 references)
PMID:18179898 SUPPORT Human Clinical
"This resulted in detection of three rare novel variants in exon 15 of UBE1 that segregate with disease"
Identifies UBA1 (UBE1) exon 15 variants segregating with XL-SMA as the disease-causing lesion.
PMID:39762237 SUPPORT Human Clinical
"UBA1 is an E1 ubiquitin-activating enzyme that initiates the ubiquitylation of target proteins and is thus a key component of the ubiquitin signaling pathway."
Defines UBA1 as the E1 ubiquitin-activating enzyme that initiates ubiquitylation.
PMID:39762237 SUPPORT Human Clinical
"This missense mutation was located with the AAD (active adenylation domain) of the protein, a known hotspot of SMAX2 mutations."
Locates SMAX2 mutations in the active adenylation domain of UBA1.
+ 2 more references
Candidate UBA1-Dependent Cellular Dysregulation
UBA1 is the initiating enzyme of the ubiquitin cascade, but human SMAX2 tissue has not shown a uniform decrease in ubiquitination or proteasomal degradation. Variant biochemistry instead points to allele-specific effects and possible non-catalytic mechanisms such as altered splicing or binding partners. This node keeps those candidate cellular routes explicit without projecting the decreased ubiquitination seen after experimental knockdown onto human pathology.
Downstream
Anterior Horn Motor Neuron Degeneration Human anterior-horn pathology is established, but the intervening allele-specific UBA1 mechanism is unknown.
Sensory Neuron and Tract Pathology Human sensory involvement forms a separate branch from anterior-horn motor-neuron degeneration; its UBA1-dependent route is unknown.
Cerebellar Developmental and Degenerative Abnormalities Cerebellar pathology was observed in one detailed human autopsy, but its relationship to specific UBA1 alleles is unresolved.
Skeletal Muscle-Autonomous Dysfunction Muscle-targeted knockdown supports a parallel model-only tissue-autonomous branch whose fidelity to human SMAX2 remains untested.
Show evidence (3 references)
PMID:23151135 SUPPORT Other
"UBA1 is the initial enzyme in the ubiquitination cascade and initiates the transfer of ubiquitin molecules to target proteins where they are degraded by the proteasome."
Establishes UBA1 as the apex enzyme whose activity gates proteasomal degradation of ubiquitinated proteins.
PMID:32315770 SUPPORT Other
"UBA1 is thus of fundamental importance to the modulation of ubiquitin homeostasis and to all downstream ubiquitylation-dependent cellular processes, including proteolysis through the ubiquitin-proteasome system and selective autophagy."
Links UBA1 impairment to disruption of ubiquitin homeostasis and ubiquitin-proteasome proteolysis.
PMID:29034082 SUPPORT In Vitro
"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..."
Supports keeping alternative allele-specific cellular routes open rather than asserting one ubiquitination-deficiency mechanism.
Anterior Horn Motor Neuron Degeneration
Degeneration and loss of anterior horn/ventral lower motor neurons is directly observed in human SMAX2. A detailed postmortem case additionally found sensory and cerebellar abnormalities, so the pathology should not be represented as exclusively motor neuronal.
Motor Neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Motor Neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology.
Downstream
Severe Neuromuscular Weakness and Hypotonia Motor neuron loss denervates skeletal muscle, producing congenital hypotonia, areflexia, and profound weakness.
Secondary Arthrogryposis from Fetal Akinesia In utero motor-system dysfunction can reduce fetal movement and thereby promote congenital joint contractures.
Show evidence (4 references)
PMID:17224690 SUPPORT Human Clinical
"X-linked infantile spinal-muscular atrophy (XL-SMA) is a rare disorder, which presents with the clinical characteristics of hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and death in infancy."
Defines XL-SMA pathology as loss of anterior horn cells with the characteristic clinical triad.
PMID:20301739 SUPPORT Human Clinical
"X-linked infantile spinal muscular atrophy (XL-SMA) is characterized by congenital hypotonia, areflexia, and evidence of degeneration and loss of anterior horn cells (i.e., lower motor neurons) in the spinal cord and brain stem."
Confirms degeneration and loss of lower motor neurons (anterior horn cells) in spinal cord and brainstem.
PMID:32315770 SUPPORT Other
"accumulating evidence implicating impaired UBA1 activity in a range of neurodegenerative conditions, including Parkinson's disease, Alzheimer's disease, Huntington's disease and spinal muscular atrophy"
Implicates impaired UBA1 activity in motor-neuron neurodegenerative disease including spinal muscular atrophy.
+ 1 more reference
Sensory Neuron and Tract Pathology
Neurophysiology and postmortem examination in one molecularly confirmed case showed sensory involvement in addition to the motor-neuron disease. This is modeled as a separate sensory branch, not as a consequence of anterior-horn degeneration, and its frequency across alleles is unknown.
Downstream
Sensory Nervous System Involvement The human neurophysiologic and postmortem sensory findings manifest clinically as sensory nervous system involvement.
Show evidence (2 references)
PMID:23518311 SUPPORT Human Clinical
"Neurophysiology revealed evidence of motor and sensory involvement"
Directly establishes sensory involvement alongside the motor phenotype.
PMID:23518311 SUPPORT Human Clinical
"there was widespread involvement of the sensory system"
Postmortem examination supports a distinct sensory-pathology branch.
Cerebellar Developmental and Degenerative Abnormalities
Developmental and degenerative cerebellar abnormalities were observed in one detailed molecularly confirmed autopsy. Their clinical consequences and frequency across SMAX2 genotypes are unknown.
Downstream
Cerebellar Abnormalities The observed cerebellar pathology is represented by the corresponding structural phenotype.
Show evidence (1 reference)
PMID:23518311 SUPPORT Human Clinical
"developmental and degenerative cerebellar abnormalities"
Directly documents cerebellar pathology in human SMAX2.
Severe Neuromuscular Weakness and Hypotonia
Lower-motor-neuron loss and denervation contribute to the severe congenital hypotonia, areflexia, and weakness of classic SMAX2. Progressive chest-muscle involvement produces ventilatory insufficiency. Model data leave open an additional muscle-autonomous contribution to weakness.
Motor Neuron CL:0000100 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves Motor Neuron (CL:0000100). CL:0000100 is a cell type from the Cell Ontology.
Downstream
Neonatal Hypotonia Congenital lower-motor-unit dysfunction manifests as neonatal hypotonia.
Areflexia Lower-motor-unit dysfunction produces absent deep-tendon reflexes.
Muscle Weakness Denervation and possible muscle-autonomous dysfunction produce generalized or distal weakness across the clinical spectrum.
Myopathic Facies Facial muscle weakness produces the characteristic myopathic facial appearance.
Respiratory Insufficiency Phrenic and intercostal motor unit failure compromises ventilation.
Poor Suck Bulbar and generalized weakness impair sucking and swallowing.
Scoliosis Progressive neuromuscular weakness can produce secondary spinal curvature.
Show evidence (1 reference)
PMID:20301739 SUPPORT Human Clinical
"Life span is significantly shortened because of progressive ventilatory insufficiency resulting from chest muscle involvement."
Links progressive motor-unit failure of respiratory muscles to ventilatory insufficiency and shortened life span.
Secondary Arthrogryposis from Fetal Akinesia
Prenatal motor-system dysfunction can reduce fetal movement. Chronic intrauterine immobility provides a plausible route to multiple congenital contractures. Fractures co-occur in reported cases, but their direct substrate is not established and is therefore not folded into the akinesia mechanism.
Downstream
Decreased Fetal Movement Prenatal motor-system dysfunction manifests as reduced fetal movement.
Arthrogryposis Multiplex Congenita Fetal akinesia from motor neuron loss produces multiple congenital joint contractures.
Increased Susceptibility to Fractures Fractures co-occur with congenital contractures, but the direct causal substrate is unknown.
Show evidence (2 references)
PMID:17224690 SUPPORT Human Clinical
"multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells"
Documents co-occurrence of arthrogryposis and anterior horn cell loss, supporting but not proving the fetal-akinesia route.
PMID:20301739 SUPPORT Human Clinical
"Often congenital contractures and/or fractures are present."
Confirms congenital contractures and fractures as characteristic features.
Skeletal Muscle-Autonomous Dysfunction
Muscle-targeted partial UBA1 knockdown reduces ubiquitination and muscle function in Drosophila and mice. This supports a possible muscle-autonomous contributor to SMAX2 weakness, but it has not been demonstrated in human SMAX2 muscle and does not displace the established human neuronal pathology.
skeletal muscle fiber CL:0008002 Cell Ontology (CL) Relation: this pathophysiological event involves this cell type This pathophysiological event involves skeletal muscle fiber (CL:0008002). CL:0008002 is a cell type from the Cell Ontology.
protein ubiquitination GO:0016567 Gene Ontology (GO) Relation: this pathophysiological event involves this biological process This pathophysiological event involves decreased protein ubiquitination (GO:0016567). GO:0016567 is a biological process from the Gene Ontology. ↓ DECREASED
Downstream
Severe Neuromuscular Weakness and Hypotonia Muscle-intrinsic UBA1 reduction may contribute to weakness alongside denervation.
Show evidence (1 reference)
PMID:42402962 SUPPORT Model Organism
"experimental reduction of UBA1 function solely in skeletal muscle recapitulates key disease aspects, highlighting a possible muscle-centric origin of SMAX2."
Supports a model-based muscle-autonomous hypothesis while the nonhuman systems and "possible" framing require hypothetical status.
✶

Histopathology

1
Inflammatory muscle changes with acute denervation features
Muscle biopsy in one molecularly confirmed infant showed marked inflammation with subtle acute-denervation features. This single observation does not by itself establish a primary inflammatory myopathy or a muscle-autonomous UBA1 mechanism.
Show evidence (1 reference)
PMID:23518311 SUPPORT Human Clinical
"muscle biopsy showed marked inflammatory changes with subtle features suggestive of acute denervation"
Directly reports the human muscle-biopsy finding and its denervation qualifier.
⬡

Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.
Pathograph: causal mechanism network for X-Linked Infantile Spinal Muscular Atrophy Interactive directed graph showing how pathophysiology mechanisms, phenotypes, genetic factors and variants, experimental models, environmental triggers, and treatments relate through causal and linked edges.
●

Phenotypes

16
Digestive 3
Poor Suck HP:0002033 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Poor suck (HP:0002033). HP:0002033 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:32181232 SUPPORT Human Clinical
"His other symptoms included speech difficulties, severe nasal tone, reduced distal muscle strength, areflexia, and inadequate sucking ability."
Directly documents impaired sucking rather than inferring a phenotype from feeding management.
Gastroesophageal Reflux HP:0002020 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Gastroesophageal reflux (HP:0002020). HP:0002020 is a phenotype from the Human Phenotype Ontology.
GeneReviews names reflux in treatment guidance but does not provide a cohort frequency, so no frequency band is assigned.
Show evidence (1 reference)
PMID:20301739 SUPPORT Human Clinical
"Standard treatment for gastroesophageal reflux disease."
GeneReviews explicitly identifies gastroesophageal reflux as a manifestation requiring treatment.
Constipation HP:0002019 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Constipation (HP:0002019). HP:0002019 is a phenotype from the Human Phenotype Ontology.
GeneReviews names constipation in treatment guidance but does not provide a cohort frequency, so no frequency band is assigned.
Show evidence (1 reference)
PMID:20301739 SUPPORT Human Clinical
"manage constipation with diet or medication"
GeneReviews explicitly identifies constipation as a manifestation requiring management.
Head and Neck 1
Myopathic Facies HP:0002058 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Myopathic facies (HP:0002058). HP:0002058 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23518311 SUPPORT Human Clinical
"He had a myopathic face, profound weakness, multiple contractures and areflexia."
Directly documents myopathic facial appearance in a molecularly confirmed case.
Musculoskeletal 3
Neonatal Hypotonia HP:0001319 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Neonatal hypotonia (HP:0001319). HP:0001319 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301739 SUPPORT Human Clinical
"X-linked infantile spinal muscular atrophy (XL-SMA) is characterized by congenital hypotonia, areflexia, and evidence of degeneration and loss of anterior horn cells"
GeneReviews lists congenital hypotonia as a defining feature.
Muscle Weakness HP:0001324 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Muscle weakness (HP:0001324). HP:0001324 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:23518311 SUPPORT Human Clinical
"He had a myopathic face, profound weakness, multiple contractures and areflexia."
Directly documents profound weakness in a molecularly confirmed case.
Scoliosis HP:0002650 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Scoliosis (HP:0002650), qualified as course progressive. HP:0002650 is a phenotype from the Human Phenotype Ontology.
Course: PROGRESSIVE
Show evidence (1 reference)
PMID:20301739 SUPPORT Human Clinical
"Orthopedic consultation and physical and occupational therapy to manage contractures and progressive scoliosis."
GeneReviews explicitly identifies progressive scoliosis as a treated manifestation.
Nervous System 3
Areflexia HP:0001284 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Areflexia (HP:0001284). HP:0001284 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17224690 SUPPORT Human Clinical
"presents with the clinical characteristics of hypotonia, areflexia, and multiple congenital contractures (arthrogryposis)"
Areflexia is one of the defining clinical characteristics of XL-SMA.
Sensory Nervous System Involvement Sensory neuropathy HP:0000763 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Sensory neuropathy (HP:0000763). HP:0000763 is a phenotype from the Human Phenotype Ontology.
This finding is supported by neurophysiology and postmortem examination in a detailed single case; its frequency across SMAX2 genotypes is unknown.
Show evidence (1 reference)
PMID:23518311 SUPPORT Human Clinical
"Neurophysiology revealed evidence of motor and sensory involvement"
Directly documents sensory as well as motor involvement in a molecularly confirmed case.
Periventricular White Matter Abnormalities Abnormal cerebral white matter morphology HP:0002500 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Periventricular white matter abnormalities, annotated with Abnormal cerebral white matter morphology (HP:0002500). HP:0002500 is a phenotype from the Human Phenotype Ontology.
This nonspecific MRI finding was reported in one molecularly confirmed case; its frequency and relationship to SMAX2 are unknown.
Show evidence (1 reference)
PMID:23518311 SUPPORT Human Clinical
"Brain MRI showed non-specific symmetrical periventricular white matter changes."
Directly documents the single-case imaging finding while its disease specificity remains uncertain.
Respiratory 1
Respiratory Insufficiency HP:0002093 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Respiratory insufficiency (HP:0002093). HP:0002093 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301739 SUPPORT Human Clinical
"Life span is significantly shortened because of progressive ventilatory insufficiency resulting from chest muscle involvement."
Progressive ventilatory insufficiency from chest-muscle weakness is the major cause of death.
Other 5
Loss of anterior horn cells Degeneration of anterior horn cells HP:0002398 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Degeneration of anterior horn cells (HP:0002398). HP:0002398 is a phenotype from the Human Phenotype Ontology.
Show evidence (2 references)
PMID:17224690 SUPPORT Human Clinical
"PURPOSE: X-linked infantile spinal-muscular atrophy (XL-SMA) is a rare disorder, which presents with the clinical characteristics of hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and death in infancy."
Associates the XL-SMA clinical picture with loss of anterior horn cells.
PMID:18179898 SUPPORT Human Clinical
"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."
Independent report associating the phenotype with loss of anterior horn cells.
Arthrogryposis Multiplex Congenita HP:0002804 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Arthrogryposis multiplex congenita (HP:0002804). HP:0002804 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:17224690 SUPPORT Human Clinical
"multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and death in infancy"
Multiple congenital contractures (arthrogryposis) is a cardinal feature of XL-SMA.
Increased Susceptibility to Fractures HP:0002659 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Increased susceptibility to fractures (HP:0002659). HP:0002659 is a phenotype from the Human Phenotype Ontology.
Show evidence (1 reference)
PMID:20301739 SUPPORT Human Clinical
"Often congenital contractures and/or fractures are present."
GeneReviews notes fractures as a characteristic feature of XL-SMA.
Decreased Fetal Movement HP:0001558 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Decreased fetal movement (HP:0001558), qualified as antenatal onset. HP:0001558 is a phenotype from the Human Phenotype Ontology.
Onset: ANTENATAL
Show evidence (1 reference)
PMID:23518311 SUPPORT Human Clinical
"Here we report a male infant who presented from birth with predominantly truncal hypotonia following an antenatal history of reduced fetal movements."
Documents reduced fetal movement before the congenital presentation.
Cerebellar Abnormalities Abnormal cerebellum morphology HP:0001317 Human Phenotype Ontology (HP) Relation: this clinical feature is this phenotype This clinical feature is Cerebellar abnormalities, annotated with Abnormal cerebellum morphology (HP:0001317). HP:0001317 is a phenotype from the Human Phenotype Ontology.
Developmental and degenerative cerebellar abnormalities were reported in one detailed postmortem case; their clinical expression and frequency across SMAX2 genotypes are unknown.
Show evidence (1 reference)
PMID:23518311 SUPPORT Human Clinical
"developmental and degenerative cerebellar abnormalities"
Directly documents structural cerebellar pathology in a molecularly confirmed human case.
🧬

Genetic Associations

1
UBA1 (Causative)
Gene: UBA1 hgnc:12469 HUGO Gene Nomenclature Committee (hgnc) Relation: this disease-associated gene is this gene This disease-associated gene is UBA1 (hgnc:12469). hgnc:12469 is a gene from the HUGO Gene Nomenclature Committee.
X-linked recessive inheritance
Show evidence (3 references)
PMID:18179898 SUPPORT Human Clinical
"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"
Identifies the causative UBA1 (UBE1) variants segregating with XL-SMA.
PMID:18179898 SUPPORT Human Clinical
"XL-SMA is part of a growing list of neurodegenerative disorders associated with defects in the ubiquitin-proteasome pathway"
Places XL-SMA among ubiquitin-proteasome pathway neurodegenerative disorders without proving one identical biochemical consequence for all variants.
PMID:29034082 SUPPORT In Vitro
"Our data revealed that only one of the three XL-SMA missense variants impairs the Ubiquitin-adenylating ability of Uba1."
Establishes allele-specific rather than uniform adenylation impairment among the three tested missense variants.
💊

Medical Actions

8
Respiratory and Airway Support
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Use airway-clearance and secretion-management techniques with noninvasive ventilatory support when possible; permanent invasive ventilation may be considered according to goals of care. This is supportive treatment, not an SMN-directed disease-modifying therapy.
Mechanism Target:
MODULATES Respiratory Insufficiency — Ventilatory and airway-clearance support mitigates the respiratory phenotype without correcting the UBA1 lesion.
Show evidence (1 reference)
PMID:20301739 SUPPORT Human Clinical
"provide rigorous airway clearance techniques, secretion management, and, ideally, noninvasive ventilatory support, although tracheostomy with permanent mechanical ventilation can be considered"
Supports the respiratory management measures listed here.
Nutrition and Feeding Support
Action: Nutritional SupportNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Nutritional Support (NCIT:C15433). NCIT:C15433 is a clinical intervention from the NCI Thesaurus. NCIT:C15433
Ensure adequate calories with supplementation and/or gastrostomy feeding when needed; monitor swallowing, reflux, constipation, and aspiration risk.
Mechanism Target:
MODULATES Poor Suck — Nutritional assessment and enteral support mitigate consequences of impaired sucking and swallowing.
Show evidence (1 reference)
PMID:20301739 SUPPORT Human Clinical
"Assure adequate caloric intake by caloric supplementation and/or gastrostomy feedings"
Supports active nutritional assessment and enteral support when needed.
Orthopedic and Rehabilitation Care
Action: physical therapyNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is physical therapy (NCIT:C15302). NCIT:C15302 is a clinical intervention from the NCI Thesaurus. Ontology label: Physical Therapy NCIT:C15302
Orthopedic follow-up plus physical and occupational therapy for contractures and progressive scoliosis.
Mechanism Target:
MODULATES Arthrogryposis Multiplex Congenita — Physical and occupational therapy manage the fixed contractures of arthrogryposis without correcting the UBA1 lesion.
MODULATES Scoliosis — Orthopedic follow-up with physical and occupational therapy manages progressive spinal curvature without correcting the UBA1 lesion.
Show evidence (1 reference)
PMID:20301739 SUPPORT Human Clinical
"Orthopedic consultation and physical and occupational therapy to manage contractures and progressive scoliosis."
Supports multidisciplinary orthopedic and rehabilitation management.
Orthopedic surveillance and specialist management
Category: Monitoring Action: clinical assessmentNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is clinical assessment, annotated with Clinical Evaluation (NCIT:C124351). NCIT:C124351 is a clinical intervention from the NCI Thesaurus. Ontology label: Clinical Evaluation NCIT:C124351
Arrange orthopedic consultation and longitudinal assessment of contractures and progressive spinal curvature, distinct from the rehabilitative therapy itself.
Show evidence (1 reference)
PMID:20301739 SUPPORT Human Clinical
"Orthopedic consultation and physical and occupational therapy to manage contractures and progressive scoliosis."
GeneReviews explicitly recommends orthopedic consultation in addition to therapy.
Gastroesophageal reflux management
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Apply standard clinical treatment for gastroesophageal reflux disease.
Mechanism Target:
MODULATES Gastroesophageal Reflux — Symptomatic reflux management mitigates the manifestation without altering UBA1 dysfunction.
Show evidence (1 reference)
PMID:20301739 SUPPORT Human Clinical
"Standard treatment for gastroesophageal reflux disease."
Directly states the GeneReviews management recommendation.
Constipation management
Action: supportive careNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is supportive care (NCIT:C15747). NCIT:C15747 is a clinical intervention from the NCI Thesaurus. Ontology label: Supportive Care NCIT:C15747
Manage constipation with dietary measures or medication as clinically indicated.
Mechanism Target:
MODULATES Constipation — Diet or medication mitigates constipation without altering the underlying neuromuscular disorder.
Show evidence (1 reference)
PMID:20301739 SUPPORT Human Clinical
"manage constipation with diet or medication"
Directly states the GeneReviews management recommendation.
Early multidisciplinary surveillance
Category: Monitoring Action: clinical assessmentNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is clinical assessment, annotated with Clinical Evaluation (NCIT:C124351). NCIT:C124351 is a clinical intervention from the NCI Thesaurus. Ontology label: Clinical Evaluation NCIT:C124351
Follow affected children at least monthly while severity and disease course are being established, coordinating neurology, respiratory, orthopedic, rehabilitation, nutrition, and gastrointestinal care.
Show evidence (1 reference)
PMID:20301739 SUPPORT Human Clinical
"Affected children should be followed at least monthly until the severity and disease course are more clearly delineated."
Directly states the recommended early surveillance interval.
Genetic Counseling
Action: Genetic CounselingNCI Thesaurus (NCIT) Relation: this treatment is this clinical intervention This treatment is Genetic Counseling (NCIT:C15240). NCIT:C15240 is a clinical intervention from the NCI Thesaurus. NCIT:C15240
Counsel families about X-linked transmission, the possibility of de novo variants, testing of at-risk relatives, and reproductive options.
Show evidence (1 reference)
PMID:20301739 SUPPORT Human Clinical
"Heterozygous females have a 50% chance of transmitting the pathogenic variant with each pregnancy."
Supports counseling about recurrence risk for a heterozygous female.
🔬

Biochemical Markers

1
Serum creatine kinase (INCREASED)
Context: Moderately raised in one molecularly confirmed infant; population frequency and diagnostic sensitivity are unknown.
Show evidence (1 reference)
PMID:23518311 SUPPORT Human Clinical
"Creatine kinase was moderately raised."
Directly documents a moderate creatine-kinase elevation in the reported case.
🔬

Diagnosis

3
Supportive Clinical and Electrophysiologic Assessment
No consensus clinical diagnostic criteria have been published. Congenital hypotonia, areflexia, weakness, contractures and/or fractures, male sex or X-linked segregation, EMG/NCS evidence of a neurogenic process, and negative SMN1 testing are supportive findings. They should prompt UBA1 testing but do not establish SMAX2 without a pathogenic or likely pathogenic UBA1 variant.
electromyography procedure NCIT:C38056 NCI Thesaurus (NCIT)
Show evidence (2 references)
PMID:32181232 SUPPORT Human Clinical
"The brain MRI of the proband's showed normal results but the electromyography results showed multiple peripheral neurogenic lesions."
Directly supports EMG as a supportive neurogenic finding rather than a disease-specific diagnostic test.
PMID:32181232 SUPPORT Human Clinical
"normal SMN1 molecular sequencing, and male gender in a simple case or an X-linked manner of inheritance in families with multiple patients"
Supports normal SMN1 testing as a useful exclusionary/supportive finding in the SMAX2 workup.
UBA1 Molecular Confirmation and Variant Interpretation
Establish the diagnosis in an affected male by identifying a hemizygous pathogenic or likely pathogenic UBA1 variant in the appropriate phenotype. A UBA1 variant of uncertain significance neither establishes nor excludes SMAX2; segregation, allele-specific functional data, and periodic reinterpretation are needed, especially given the heterogeneous effects of exon-15 variants.
molecular genetic testing NCIT:C19770 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20301739 SUPPORT Human Clinical
"The diagnosis of X-linked infantile spinal muscular atrophy is established in a male proband with suggestive clinical features and a hemizygous pathogenic variant in UBA1 identified by molecular genetic testing."
Establishes the required clinical-plus-pathogenic-variant basis while excluding a VUS-only result from confirmation.
Family Variant Testing and Recurrence Counseling
Once a familial UBA1 pathogenic variant is known, test at-risk female relatives; prenatal and preimplantation genetic testing are possible. Counseling should explain that de novo variants occur, heterozygous females are usually but not invariably unaffected, and a negative maternal blood test does not reduce recurrence risk to zero because maternal germline mosaicism remains possible.
genetic testing NCIT:C15709 NCI Thesaurus (NCIT)
Show evidence (1 reference)
PMID:20301739 SUPPORT Human Clinical
"Once the UBA1 pathogenic variant has been identified in an affected family member, carrier testing for at risk female relatives and prenatal and preimplantation genetic testing are possible."
Supports cascade carrier testing and reproductive testing after variant identification.
📈

Progression

3
Prenatal presentation
Age: Fetal period
Reduced fetal movement can precede the congenital neuromuscular phenotype.
Show evidence (1 reference)
PMID:23518311 SUPPORT Human Clinical
"Here we report a male infant who presented from birth with predominantly truncal hypotonia following an antenatal history of reduced fetal movements."
Documents prenatal reduced movement followed by hypotonia at birth in a molecularly confirmed male.
Classic severe infantile course
Age: Birth through infancy
Classic reported cases show congenital weakness and contractures followed by progressive respiratory failure and early death, but this should not be read as a universal survival estimate for every UBA1 genotype.
Show evidence (1 reference)
PMID:23518311 SUPPORT Human Clinical
"He died from progressive respiratory failure at 4 months."
Provides a directly observed severe natural-history example without converting a single case into a population survival rate.
Broader recognized spectrum
Age: Infancy through adulthood
Molecularly confirmed families include a mild, nonprogressive branch with autonomous adult survival as well as longer-surviving children with expanded manifestations. Lethal neonatal or early-infantile presentation is therefore not an adequate ascertainment definition, and prognosis should be interpreted allele by allele and family by family.
Show evidence (4 references)
PMID:32181232 SUPPORT Human Clinical
"The phenomenon was not progressively aggravated, and they had the ability to live on their own as adults."
Directly documents a nonprogressive, independently living adult-surviving SMAX2 branch in the p.Met539Ile family.
PMID:32181232 SUPPORT Human Clinical
"They presented similar symptoms and had experienced a long and autonomous life."
The abstract independently summarizes extended autonomous survival among affected males in the family.
PMID:35707597 SUPPORT Human Clinical
"Our study presents the first patients from Turkey, widening the phenotypic spectrum of SMAX2 by pectus carinatum, medullary sponge kidney, and frontal cyst."
Supports a broader molecularly confirmed clinical spectrum beyond the original lethal-infantile description.
+ 1 more reference
📊

Prevalence

1
Worldwide
Unknown Rare
No population-based prevalence or birth-incidence estimate is established in the cited literature. Published reports repeatedly describe SMAX2 as rare and are dominated by affected male probands and multiplex X-linked families; this record therefore avoids a numeric rate.
Show evidence (1 reference)
PMID:17224690 SUPPORT Human Clinical
"X-linked infantile spinal-muscular atrophy (XL-SMA) is a rare disorder"
Supports only the qualitative rare classification; it does not provide a population rate.
🔀

Differential Diagnoses

6

Conditions with similar clinical presentations that must be differentiated from X-Linked Infantile Spinal Muscular Atrophy:

Kennedy Disease MONDO:0010735
Overlapping Features Kennedy disease (X-linked spinal and bulbar muscular atrophy, SBMA) is also an X-linked lower motor neuron disease, but is adult-onset and caused by an androgen-receptor (AR) CAG trinucleotide repeat expansion, not an infantile exon-15 UBA1 variant, and lacks the congenital arthrogryposis and infantile lethality of SMAX2.
Distinguishing Features
  • Adult midlife onset in Kennedy disease versus congenital/infantile onset in SMAX2.
  • AR CAG expansion versus an SMAX2-associated UBA1 variant.
  • Absence of congenital contractures/arthrogryposis in Kennedy disease.
Show evidence (2 references)
PMID:20301508 SUPPORT Human Clinical
"The diagnosis of SBMA is established in a male proband by the identification of a hemizygous expansion of a CAG trinucleotide repeat (>35 CAGs) in AR by molecular genetic testing."
Directly supports the AR CAG-repeat molecular discriminator for Kennedy disease.
PMID:20301508 SUPPORT Human Clinical
"Spinal and bulbar muscular atrophy (SBMA) is a gradually progressive neuromuscular disorder in which degeneration of lower motor neurons results in muscle weakness, muscle atrophy, and fasciculations in affected males."
Supports the gradually progressive motor-neuron phenotype that contrasts with congenital SMAX2.
X-Linked Distal Spinal Muscular Atrophy Type 3 Not Yet Curated MONDO:0010338
Overlapping Features SMAX3 is an ATP7A-related distal hereditary motor neuropathy with progressive distal weakness and atrophy. It is distinguished from congenital SMAX2 by its ATP7A basis, distal distribution, and generally later, slower course.
Distinguishing Features
  • Pathogenic ATP7A variants favor SMAX3; pathogenic UBA1 variants favor SMAX2.
  • Distal progressive gait and hand/foot involvement favor SMAX3 over congenital generalized weakness with arthrogryposis.
Show evidence (2 references)
PMID:20170900 SUPPORT Human Clinical
"We identified two unique ATP7A missense mutations (p.P1386S and p.T994I) in males with distal motor neuropathy in two families."
Primary human-family evidence directly establishes the ATP7A basis of the distal motor neuropathy.
PMID:20170900 SUPPORT Human Clinical
"certain missense mutations at this locus can cause a syndrome restricted to progressive distal motor neuropathy without overt signs of systemic copper deficiency."
Directly supports the progressive distal distribution and absence of systemic copper-deficiency signs.
Spinal Muscular Atrophy with Respiratory Distress Type 1 MONDO:0011436
Overlapping Features SMARD1 is an autosomal recessive IGHMBP2 disorder with early respiratory failure and motor weakness. Diaphragmatic palsy and distal-predominant weakness favor SMARD1; congenital arthrogryposis/fractures, X-linked segregation, and a hemizygous UBA1 variant favor SMAX2.
Distinguishing Features
  • Biallelic IGHMBP2 variants and autosomal recessive inheritance favor SMARD1.
  • Early diaphragmatic palsy with distal weakness favors SMARD1.
Show evidence (2 references)
PMID:11528396 SUPPORT Human Clinical
"Here we demonstrate that SMARD type 1 (SMARD1) results from mutations in the gene encoding immunoglobulin micro-binding protein 2 (IGHMBP2; on chromosome 11q13.2-q13.4)."
Supports the distinct IGHMBP2 genetic basis of SMARD1.
PMID:35611426 SUPPORT Human Clinical
"The initial symptoms of patients with SMARD1 are respiratory distress and distal muscle weakness manifesting in the infantile period due to progressive degeneration of α-motor neurons."
Directly supports early respiratory distress and distal-predominant weakness as clinical discriminators.
Spinal Muscular Atrophy with Congenital Bone Fractures 2 Not Yet Curated MONDO:0014807
Overlapping Features ASCC1-related SMABF2 can closely mimic SMAX2 through prenatal or neonatal hypotonia, congenital contractures, long-bone fractures, pulmonary hypoplasia, and respiratory distress. Biallelic ASCC1 variants and autosomal recessive inheritance favor SMABF2; a hemizygous UBA1 pathogenic variant and X-linked segregation favor SMAX2.
Distinguishing Features
  • Biallelic ASCC1 variants and autosomal recessive inheritance favor SMABF2.
  • Prenatal long-bone fractures, congenital contractures, and respiratory distress overlap substantially and require molecular discrimination.
Show evidence (1 reference)
PMID:33931933 SUPPORT Human Clinical
"Spinal muscular atrophy with congenital bone fractures 2 (SMABF2), a type of arthrogryposis multiplex congenita (AMC), is characterized by congenital joint contractures, prenatal fractures of long bones, and respiratory distress and results from biallelic variants in ASCC1."
Directly supports both the overlapping phenotype and the distinct biallelic ASCC1 etiology.
{ }

Source YAML

click to show 
name: X-Linked Infantile Spinal Muscular Atrophy
creation_date: "2026-06-26T00:00:00Z"
category: Mendelian
description: >-
  X-linked infantile spinal muscular atrophy (XL-SMA; SMAX2; X-linked spinal
  muscular atrophy with arthrogryposis) is a rare UBA1-related neuromuscular
  disorder. Classic cases are hemizygous males with prenatal or neonatal onset of
  reduced fetal movement, severe hypotonia, areflexia, weakness, arthrogryposis,
  fractures, and progressive ventilatory failure. Most reported familial cases
  follow X-linked transmission through usually unaffected heterozygous females,
  although de novo hemizygous variants also occur. Human neuropathology confirms
  severe ventral/anterior-horn motor-neuron loss; one detailed autopsy also found
  sensory-system and cerebellar involvement, arguing that SMAX2 need not be a pure
  anterior-horn-cell disorder. UBA1 initiates ubiquitination, and the original
  synonymous allele reduces UBA1 expression, but the tissue and downstream pathway
  that determine selective neuromuscular injury remain unsettled. Model-organism
  work supports both neuronal proteostasis and muscle-autonomous contributions.
  SMAX2 is distinct from SMN1-related proximal SMA, AR-related Kennedy disease,
  ATP7A-related X-linked distal SMA type 3, and the recently described adult-onset
  UBA1-related non-Kennedy spinal-bulbar muscular atrophy.
parents:
- Motor Neuron Disease
disease_term:
  preferred_term: X-linked infantile spinal muscular atrophy
  term:
    id: MONDO:0010532
    label: infantile-onset X-linked spinal muscular atrophy
references:
- reference: PMID:17224690
  title: "X-linked infantile spinal muscular atrophy: clinical definition and molecular mapping."
- reference: PMID:18179898
  title: "Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy."
- reference: PMID:23518311
  title: "Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene."
- reference: PMID:20301739
  title: "Spinal Muscular Atrophy, X-Linked Infantile."
  tags:
  - GeneReviews
inheritance:
- name: X-linked recessive inheritance
  inheritance_term:
    preferred_term: X-linked recessive inheritance
    term:
      id: HP:0001419
      label: X-linked recessive inheritance
  evidence:
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "By definition, XL-SMA is inherited in an X-linked manner."
    explanation: GeneReviews establishes X-linked inheritance for XL-SMA.
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Males who inherit the pathogenic variant will be affected; females who inherit the pathogenic variant will be heterozygotes and will usually not be affected."
    explanation: Confirms affected males and usually-unaffected carrier females, consistent with X-linked recessive inheritance.
  - reference: PMID:39762237
    reference_title: "A novel UBA1 gene mutation in a patient with infantile respiratory distress syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified a de novo hemizygous mutation, c.1660 C > T (p.Pro554Ser), in exon 15 of the UBA1 gene in this baby."
    explanation: Demonstrates that an affected male may carry a de novo hemizygous UBA1 variant rather than an inherited maternal allele.
prevalence:
- population: Worldwide
  measure_type: UNKNOWN
  prevalence_class: RARE
  notes: >-
    No population-based prevalence or birth-incidence estimate is established in
    the cited literature. Published reports repeatedly describe SMAX2 as rare and
    are dominated by affected male probands and multiplex X-linked families; this
    record therefore avoids a numeric rate.
  evidence:
  - reference: PMID:17224690
    reference_title: "X-linked infantile spinal muscular atrophy: clinical definition and molecular mapping."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "X-linked infantile spinal-muscular atrophy (XL-SMA) is a rare disorder"
    explanation: Supports only the qualitative rare classification; it does not provide a population rate.
progression:
- phase: Prenatal presentation
  age_range: Fetal period
  notes: Reduced fetal movement can precede the congenital neuromuscular phenotype.
  evidence:
  - reference: PMID:23518311
    reference_title: "Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report a male infant who presented from birth with predominantly truncal hypotonia following an antenatal history of reduced fetal movements."
    explanation: Documents prenatal reduced movement followed by hypotonia at birth in a molecularly confirmed male.
- phase: Classic severe infantile course
  age_range: Birth through infancy
  notes: >-
    Classic reported cases show congenital weakness and contractures followed by
    progressive respiratory failure and early death, but this should not be read as
    a universal survival estimate for every UBA1 genotype.
  evidence:
  - reference: PMID:23518311
    reference_title: "Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He died from progressive respiratory failure at 4 months."
    explanation: Provides a directly observed severe natural-history example without converting a single case into a population survival rate.
- phase: Broader recognized spectrum
  age_range: Infancy through adulthood
  notes: >-
    Molecularly confirmed families include a mild, nonprogressive branch with
    autonomous adult survival as well as longer-surviving children with expanded
    manifestations. Lethal neonatal or early-infantile presentation is therefore
    not an adequate ascertainment definition, and prognosis should be interpreted
    allele by allele and family by family.
  evidence:
  - reference: PMID:32181232
    reference_title: "A Pathogenic Missense Variant (c.1617G>A, p.Met539Ile) in UBA1 Causing Infantile X-Linked Spinal Muscular Atrophy (SMAX2)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The phenomenon was not progressively aggravated, and they had the ability to live on their own as adults."
    explanation: Directly documents a nonprogressive, independently living adult-surviving SMAX2 branch in the p.Met539Ile family.
  - reference: PMID:32181232
    reference_title: "A Pathogenic Missense Variant (c.1617G>A, p.Met539Ile) in UBA1 Causing Infantile X-Linked Spinal Muscular Atrophy (SMAX2)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "They presented similar symptoms and had experienced a long and autonomous life."
    explanation: The abstract independently summarizes extended autonomous survival among affected males in the family.
  - reference: PMID:35707597
    reference_title: "X-Linked Spinal Muscular Atrophy 2 due to a Synonymous Variant in the UBA1 Gene in a Family with Novel Findings from Turkey."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our study presents the first patients from Turkey, widening the phenotypic spectrum of SMAX2 by pectus carinatum, medullary sponge kidney, and frontal cyst."
    explanation: Supports a broader molecularly confirmed clinical spectrum beyond the original lethal-infantile description.
  - reference: PMID:39762237
    reference_title: "A novel UBA1 gene mutation in a patient with infantile respiratory distress syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We here report a case of infantile respiratory distress syndrome followed by continuing neuromuscular symptoms."
    explanation: Supports a molecularly confirmed presentation with continuing neuromuscular manifestations rather than immediate infantile death.
pathophysiology:
- name: Allele-Specific UBA1 Dysfunction
  biological_scale: MOLECULAR
  mechanism_confidence: PROVISIONAL
  description: >-
    SMAX2-associated hemizygous variants cluster in exon 15 near the active
    adenylation domain, but they do not share one demonstrated biochemical defect.
    The recurrent synonymous c.1731C>T allele reduces UBA1 expression. In vitro,
    p.Met539Ile and p.Ser547Gly did not show statistically reduced adenylation,
    whereas p.Glu557Val showed a moderate reduction. The initiating lesion is
    therefore modeled as allele-specific UBA1 dysfunction rather than uniform
    adenylation failure or complete loss of UBA1 function.
  evidence:
  - reference: PMID:18179898
    reference_title: "Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This resulted in detection of three rare novel variants in exon 15 of UBE1 that segregate with disease"
    explanation: Identifies UBA1 (UBE1) exon 15 variants segregating with XL-SMA as the disease-causing lesion.
  - reference: PMID:39762237
    reference_title: "A novel UBA1 gene mutation in a patient with infantile respiratory distress syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "UBA1 is an E1 ubiquitin-activating enzyme that initiates the ubiquitylation of target proteins and is thus a key component of the ubiquitin signaling pathway."
    explanation: Defines UBA1 as the E1 ubiquitin-activating enzyme that initiates ubiquitylation.
  - reference: PMID:39762237
    reference_title: "A novel UBA1 gene mutation in a patient with infantile respiratory distress syndrome."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This missense mutation was located with the AAD (active adenylation domain) of the protein, a known hotspot of SMAX2 mutations."
    explanation: Locates SMAX2 mutations in the active adenylation domain of UBA1.
  - reference: PMID:18179898
    reference_title: "Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We also demonstrated that the synonymous C-->T substitution leads to significant reduction of UBE1 expression and alters the methylation pattern of exon 15"
    explanation: Directly supports reduced expression for the recurrent synonymous allele, not a blanket loss-of-function assignment for every missense allele.
  - reference: PMID:29034082
    reference_title: "Functional characterizations of rare UBA1 variants in X-linked Spinal Muscular Atrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Missense variants p.M539I and p.S547G showed no statistically-reduced adenylation activity, despite their locations in the well-conserved AAD, while variant p.E557V showed a moderate decrease in activity"
    explanation: Directly distinguishes the preserved adenylation of p.Met539I/p.Ser547Gly from the moderate p.Glu557Val defect.
  downstream:
  - target: Candidate UBA1-Dependent Cellular Dysregulation
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Different alleles may perturb splicing, binding partners, ubiquitin handling, or other UBA1-dependent processes through mechanisms not yet established in patient tissue.
- name: Candidate UBA1-Dependent Cellular Dysregulation
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    UBA1 is the initiating enzyme of the ubiquitin cascade, but human SMAX2 tissue
    has not shown a uniform decrease in ubiquitination or proteasomal degradation.
    Variant biochemistry instead points to allele-specific effects and possible
    non-catalytic mechanisms such as altered splicing or binding partners. This
    node keeps those candidate cellular routes explicit without projecting the
    decreased ubiquitination seen after experimental knockdown onto human pathology.
  evidence:
  - reference: PMID:23151135
    reference_title: "Targeting the ubiquitin E1 as a novel anti-cancer strategy."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "UBA1 is the initial enzyme in the ubiquitination cascade and initiates the transfer of ubiquitin molecules to target proteins where they are degraded by the proteasome."
    explanation: Establishes UBA1 as the apex enzyme whose activity gates proteasomal degradation of ubiquitinated proteins.
  - reference: PMID:32315770
    reference_title: "The pivotal role of ubiquitin-activating enzyme E1 (UBA1) in neuronal health and neurodegeneration."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "UBA1 is thus of fundamental importance to the modulation of ubiquitin homeostasis and to all downstream ubiquitylation-dependent cellular processes, including proteolysis through the ubiquitin-proteasome system and selective autophagy."
    explanation: Links UBA1 impairment to disruption of ubiquitin homeostasis and ubiquitin-proteasome proteolysis.
  - reference: PMID:29034082
    reference_title: "Functional characterizations of rare UBA1 variants in X-linked Spinal Muscular Atrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "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."
    explanation: Supports keeping alternative allele-specific cellular routes open rather than asserting one ubiquitination-deficiency mechanism.
  downstream:
  - target: Anterior Horn Motor Neuron Degeneration
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Human anterior-horn pathology is established, but the intervening allele-specific UBA1 mechanism is unknown.
  - target: Sensory Neuron and Tract Pathology
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Human sensory involvement forms a separate branch from anterior-horn motor-neuron degeneration; its UBA1-dependent route is unknown.
  - target: Cerebellar Developmental and Degenerative Abnormalities
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Cerebellar pathology was observed in one detailed human autopsy, but its relationship to specific UBA1 alleles is unresolved.
  - target: Skeletal Muscle-Autonomous Dysfunction
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Muscle-targeted knockdown supports a parallel model-only tissue-autonomous branch whose fidelity to human SMAX2 remains untested.
- name: Anterior Horn Motor Neuron Degeneration
  biological_scale: CELLULAR
  description: >-
    Degeneration and loss of anterior horn/ventral lower motor neurons is directly
    observed in human SMAX2. A detailed postmortem case additionally found sensory
    and cerebellar abnormalities, so the pathology should not be represented as
    exclusively motor neuronal.
  cell_types:
  - preferred_term: Motor Neuron
    term:
      id: CL:0000100
      label: motor neuron
  evidence:
  - reference: PMID:17224690
    reference_title: "X-linked infantile spinal muscular atrophy: clinical definition and molecular mapping."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "X-linked infantile spinal-muscular atrophy (XL-SMA) is a rare disorder, which presents with the clinical characteristics of hypotonia, areflexia, and multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and death in infancy."
    explanation: Defines XL-SMA pathology as loss of anterior horn cells with the characteristic clinical triad.
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "X-linked infantile spinal muscular atrophy (XL-SMA) is characterized by congenital hypotonia, areflexia, and evidence of degeneration and loss of anterior horn cells (i.e., lower motor neurons) in the spinal cord and brain stem."
    explanation: Confirms degeneration and loss of lower motor neurons (anterior horn cells) in spinal cord and brainstem.
  - reference: PMID:32315770
    reference_title: "The pivotal role of ubiquitin-activating enzyme E1 (UBA1) in neuronal health and neurodegeneration."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "accumulating evidence implicating impaired UBA1 activity in a range of neurodegenerative conditions, including Parkinson's disease, Alzheimer's disease, Huntington's disease and spinal muscular atrophy"
    explanation: Implicates impaired UBA1 activity in motor-neuron neurodegenerative disease including spinal muscular atrophy.
  - reference: PMID:23518311
    reference_title: "Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: Defines the broader human neuropathology and prevents overclassification as a pure anterior-horn-cell disease.
  downstream:
  - target: Severe Neuromuscular Weakness and Hypotonia
    description: Motor neuron loss denervates skeletal muscle, producing congenital hypotonia, areflexia, and profound weakness.
  - target: Secondary Arthrogryposis from Fetal Akinesia
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Reduced fetal movement and prolonged joint immobility
    description: In utero motor-system dysfunction can reduce fetal movement and thereby promote congenital joint contractures.
- name: Sensory Neuron and Tract Pathology
  biological_scale: CELLULAR
  description: >-
    Neurophysiology and postmortem examination in one molecularly confirmed case
    showed sensory involvement in addition to the motor-neuron disease. This is
    modeled as a separate sensory branch, not as a consequence of anterior-horn
    degeneration, and its frequency across alleles is unknown.
  evidence:
  - reference: PMID:23518311
    reference_title: "Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurophysiology revealed evidence of motor and sensory involvement"
    explanation: Directly establishes sensory involvement alongside the motor phenotype.
  - reference: PMID:23518311
    reference_title: "Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "there was widespread involvement of the sensory system"
    explanation: Postmortem examination supports a distinct sensory-pathology branch.
  downstream:
  - target: Sensory Nervous System Involvement
    causal_link_type: DIRECT
    description: The human neurophysiologic and postmortem sensory findings manifest clinically as sensory nervous system involvement.
- name: Cerebellar Developmental and Degenerative Abnormalities
  biological_scale: TISSUE
  description: >-
    Developmental and degenerative cerebellar abnormalities were observed in one
    detailed molecularly confirmed autopsy. Their clinical consequences and
    frequency across SMAX2 genotypes are unknown.
  evidence:
  - reference: PMID:23518311
    reference_title: "Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developmental and degenerative cerebellar abnormalities"
    explanation: Directly documents cerebellar pathology in human SMAX2.
  downstream:
  - target: Cerebellar Abnormalities
    causal_link_type: DIRECT
    description: The observed cerebellar pathology is represented by the corresponding structural phenotype.
- name: Severe Neuromuscular Weakness and Hypotonia
  biological_scale: ORGANISM
  description: >-
    Lower-motor-neuron loss and denervation contribute to the severe congenital
    hypotonia, areflexia, and weakness of classic SMAX2. Progressive chest-muscle
    involvement produces ventilatory insufficiency. Model data leave open an
    additional muscle-autonomous contribution to weakness.
  cell_types:
  - preferred_term: Motor Neuron
    term:
      id: CL:0000100
      label: motor neuron
  evidence:
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Life span is significantly shortened because of progressive ventilatory insufficiency resulting from chest muscle involvement."
    explanation: Links progressive motor-unit failure of respiratory muscles to ventilatory insufficiency and shortened life span.
  downstream:
  - target: Neonatal Hypotonia
    description: Congenital lower-motor-unit dysfunction manifests as neonatal hypotonia.
  - target: Areflexia
    description: Lower-motor-unit dysfunction produces absent deep-tendon reflexes.
  - target: Muscle Weakness
    description: Denervation and possible muscle-autonomous dysfunction produce generalized or distal weakness across the clinical spectrum.
  - target: Myopathic Facies
    description: Facial muscle weakness produces the characteristic myopathic facial appearance.
  - target: Respiratory Insufficiency
    description: Phrenic and intercostal motor unit failure compromises ventilation.
  - target: Poor Suck
    description: Bulbar and generalized weakness impair sucking and swallowing.
  - target: Scoliosis
    causal_link_type: INDIRECT_KNOWN_INTERMEDIATES
    intermediate_mechanisms:
    - Chronic axial weakness and asymmetric loading during growth.
    description: Progressive neuromuscular weakness can produce secondary spinal curvature.
- name: Secondary Arthrogryposis from Fetal Akinesia
  biological_scale: TISSUE
  mechanism_confidence: PROVISIONAL
  description: >-
    Prenatal motor-system dysfunction can reduce fetal movement. Chronic
    intrauterine immobility provides a plausible route to multiple congenital
    contractures. Fractures co-occur in reported cases, but their direct substrate
    is not established and is therefore not folded into the akinesia mechanism.
  evidence:
  - reference: PMID:17224690
    reference_title: "X-linked infantile spinal muscular atrophy: clinical definition and molecular mapping."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells"
    explanation: Documents co-occurrence of arthrogryposis and anterior horn cell loss, supporting but not proving the fetal-akinesia route.
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Often congenital contractures and/or fractures are present."
    explanation: Confirms congenital contractures and fractures as characteristic features.
  downstream:
  - target: Decreased Fetal Movement
    description: Prenatal motor-system dysfunction manifests as reduced fetal movement.
  - target: Arthrogryposis Multiplex Congenita
    description: Fetal akinesia from motor neuron loss produces multiple congenital joint contractures.
  - target: Increased Susceptibility to Fractures
    causal_link_type: UNKNOWN
    description: Fractures co-occur with congenital contractures, but the direct causal substrate is unknown.
- name: Skeletal Muscle-Autonomous Dysfunction
  biological_scale: TISSUE
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Muscle-targeted partial UBA1 knockdown reduces ubiquitination and muscle
    function in Drosophila and mice. This supports a possible muscle-autonomous
    contributor to SMAX2 weakness, but it has not been demonstrated in human SMAX2
    muscle and does not displace the established human neuronal pathology.
  cell_types:
  - preferred_term: skeletal muscle fiber
    term:
      id: CL:0008002
      label: skeletal muscle fiber
  biological_processes:
  - preferred_term: protein ubiquitination
    term:
      id: GO:0016567
      label: protein ubiquitination
    modifier: DECREASED
  evidence:
  - reference: PMID:42402962
    reference_title: "UBA1 knockdown dysregulates the levels of UBA1-sensitive proteins and impairs muscle function in Drosophila and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "experimental reduction of UBA1 function solely in skeletal muscle recapitulates key disease aspects, highlighting a possible muscle-centric origin of SMAX2."
    explanation: Supports a model-based muscle-autonomous hypothesis while the nonhuman systems and "possible" framing require hypothetical status.
  downstream:
  - target: Severe Neuromuscular Weakness and Hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Muscle-intrinsic UBA1 reduction may contribute to weakness alongside denervation.
phenotypes:
- name: Loss of anterior horn cells
  category: Neurological
  description: >-
    UBA1 deficiency degenerates the spinal anterior horn cells, producing congenital
    hypotonia, areflexia, and arthrogryposis.
  phenotype_term:
    preferred_term: Degeneration of anterior horn cells
    term:
      id: HP:0002398
      label: Degeneration of anterior horn cells
  evidence:
  - reference: PMID:17224690
    reference_title: "X-linked infantile spinal muscular atrophy: clinical definition and molecular mapping."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "PURPOSE: X-linked infantile spinal-muscular atrophy (XL-SMA) is a rare disorder,
      which presents with the clinical characteristics of hypotonia, areflexia, and
      multiple congenital contractures (arthrogryposis) associated with loss of
      anterior horn cells and death in infancy."
    explanation: >-
      Associates the XL-SMA clinical picture with loss of anterior horn cells.
  - reference: PMID:18179898
    reference_title: "Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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."
    explanation: >-
      Independent report associating the phenotype with loss of anterior horn cells.
- name: Neonatal Hypotonia
  category: Neurological
  diagnostic: true
  phenotype_term:
    preferred_term: Neonatal hypotonia
    term:
      id: HP:0001319
      label: Neonatal hypotonia
  evidence:
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "X-linked infantile spinal muscular atrophy (XL-SMA) is characterized by congenital hypotonia, areflexia, and evidence of degeneration and loss of anterior horn cells"
    explanation: GeneReviews lists congenital hypotonia as a defining feature.
- name: Areflexia
  category: Neurological
  diagnostic: true
  phenotype_term:
    preferred_term: Areflexia
    term:
      id: HP:0001284
      label: Areflexia
  evidence:
  - reference: PMID:17224690
    reference_title: "X-linked infantile spinal muscular atrophy: clinical definition and molecular mapping."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "presents with the clinical characteristics of hypotonia, areflexia, and multiple congenital contractures (arthrogryposis)"
    explanation: Areflexia is one of the defining clinical characteristics of XL-SMA.
- name: Muscle Weakness
  category: Musculoskeletal
  diagnostic: true
  phenotype_term:
    preferred_term: Muscle weakness
    term:
      id: HP:0001324
      label: Muscle weakness
  evidence:
  - reference: PMID:23518311
    reference_title: "Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had a myopathic face, profound weakness, multiple contractures and areflexia."
    explanation: Directly documents profound weakness in a molecularly confirmed case.
- name: Arthrogryposis Multiplex Congenita
  category: Musculoskeletal
  diagnostic: true
  phenotype_term:
    preferred_term: Arthrogryposis multiplex congenita
    term:
      id: HP:0002804
      label: Arthrogryposis multiplex congenita
  evidence:
  - reference: PMID:17224690
    reference_title: "X-linked infantile spinal muscular atrophy: clinical definition and molecular mapping."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "multiple congenital contractures (arthrogryposis) associated with loss of anterior horn cells and death in infancy"
    explanation: Multiple congenital contractures (arthrogryposis) is a cardinal feature of XL-SMA.
- name: Increased Susceptibility to Fractures
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Increased susceptibility to fractures
    term:
      id: HP:0002659
      label: Increased susceptibility to fractures
  evidence:
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Often congenital contractures and/or fractures are present."
    explanation: GeneReviews notes fractures as a characteristic feature of XL-SMA.
- name: Respiratory Insufficiency
  category: Respiratory
  phenotype_term:
    preferred_term: Respiratory insufficiency
    term:
      id: HP:0002093
      label: Respiratory insufficiency
  evidence:
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Life span is significantly shortened because of progressive ventilatory insufficiency resulting from chest muscle involvement."
    explanation: Progressive ventilatory insufficiency from chest-muscle weakness is the major cause of death.
- name: Poor Suck
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Poor suck
    term:
      id: HP:0002033
      label: Poor suck
  evidence:
  - reference: PMID:32181232
    reference_title: "A Pathogenic Missense Variant (c.1617G>A, p.Met539Ile) in UBA1 Causing Infantile X-Linked Spinal Muscular Atrophy (SMAX2)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "His other symptoms included speech difficulties, severe nasal tone, reduced distal muscle strength, areflexia, and inadequate sucking ability."
    explanation: Directly documents impaired sucking rather than inferring a phenotype from feeding management.
- name: Decreased Fetal Movement
  category: Prenatal
  phenotype_term:
    preferred_term: Decreased fetal movement
    term:
      id: HP:0001558
      label: Decreased fetal movement
    onset:
      onset_category: ANTENATAL
  evidence:
  - reference: PMID:23518311
    reference_title: "Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we report a male infant who presented from birth with predominantly truncal hypotonia following an antenatal history of reduced fetal movements."
    explanation: Documents reduced fetal movement before the congenital presentation.
- name: Myopathic Facies
  category: Craniofacial
  phenotype_term:
    preferred_term: Myopathic facies
    term:
      id: HP:0002058
      label: Myopathic facies
  evidence:
  - reference: PMID:23518311
    reference_title: "Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "He had a myopathic face, profound weakness, multiple contractures and areflexia."
    explanation: Directly documents myopathic facial appearance in a molecularly confirmed case.
- name: Sensory Nervous System Involvement
  category: Neurological
  phenotype_term:
    preferred_term: Sensory neuropathy
    term:
      id: HP:0000763
      label: Sensory neuropathy
  notes: >-
    This finding is supported by neurophysiology and postmortem examination in a
    detailed single case; its frequency across SMAX2 genotypes is unknown.
  evidence:
  - reference: PMID:23518311
    reference_title: "Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Neurophysiology revealed evidence of motor and sensory involvement"
    explanation: Directly documents sensory as well as motor involvement in a molecularly confirmed case.
- name: Cerebellar Abnormalities
  category: Neurological
  phenotype_term:
    preferred_term: Cerebellar abnormalities
    term:
      id: HP:0001317
      label: Abnormal cerebellum morphology
  notes: >-
    Developmental and degenerative cerebellar abnormalities were reported in one
    detailed postmortem case; their clinical expression and frequency across
    SMAX2 genotypes are unknown.
  evidence:
  - reference: PMID:23518311
    reference_title: "Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developmental and degenerative cerebellar abnormalities"
    explanation: Directly documents structural cerebellar pathology in a molecularly confirmed human case.
- name: Scoliosis
  category: Musculoskeletal
  phenotype_term:
    preferred_term: Scoliosis
    term:
      id: HP:0002650
      label: Scoliosis
    clinical_course: PROGRESSIVE
  evidence:
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Orthopedic consultation and physical and occupational therapy to manage contractures and progressive scoliosis."
    explanation: GeneReviews explicitly identifies progressive scoliosis as a treated manifestation.
- name: Gastroesophageal Reflux
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Gastroesophageal reflux
    term:
      id: HP:0002020
      label: Gastroesophageal reflux
  notes: >-
    GeneReviews names reflux in treatment guidance but does not provide a cohort
    frequency, so no frequency band is assigned.
  evidence:
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Standard treatment for gastroesophageal reflux disease."
    explanation: GeneReviews explicitly identifies gastroesophageal reflux as a manifestation requiring treatment.
- name: Constipation
  category: Gastrointestinal
  phenotype_term:
    preferred_term: Constipation
    term:
      id: HP:0002019
      label: Constipation
  notes: >-
    GeneReviews names constipation in treatment guidance but does not provide a
    cohort frequency, so no frequency band is assigned.
  evidence:
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manage constipation with diet or medication"
    explanation: GeneReviews explicitly identifies constipation as a manifestation requiring management.
- name: Periventricular White Matter Abnormalities
  category: Neurological
  phenotype_term:
    preferred_term: Periventricular white matter abnormalities
    term:
      id: HP:0002500
      label: Abnormal cerebral white matter morphology
  notes: >-
    This nonspecific MRI finding was reported in one molecularly confirmed case;
    its frequency and relationship to SMAX2 are unknown.
  evidence:
  - reference: PMID:23518311
    reference_title: "Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Brain MRI showed non-specific symmetrical periventricular white matter changes."
    explanation: Directly documents the single-case imaging finding while its disease specificity remains uncertain.
histopathology:
- name: Inflammatory muscle changes with acute denervation features
  description: >-
    Muscle biopsy in one molecularly confirmed infant showed marked inflammation
    with subtle acute-denervation features. This single observation does not by
    itself establish a primary inflammatory myopathy or a muscle-autonomous UBA1 mechanism.
  evidence:
  - reference: PMID:23518311
    reference_title: "Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "muscle biopsy showed marked inflammatory changes with subtle features suggestive of acute denervation"
    explanation: Directly reports the human muscle-biopsy finding and its denervation qualifier.
biochemical:
- name: Serum creatine kinase
  presence: INCREASED
  context: >-
    Moderately raised in one molecularly confirmed infant; population frequency
    and diagnostic sensitivity are unknown.
  evidence:
  - reference: PMID:23518311
    reference_title: "Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Creatine kinase was moderately raised."
    explanation: Directly documents a moderate creatine-kinase elevation in the reported case.
genetic:
- name: UBA1
  association: Causative
  inheritance:
  - name: X-linked recessive inheritance
    inheritance_term:
      preferred_term: X-linked recessive inheritance
      term:
        id: HP:0001419
        label: X-linked recessive inheritance
  gene_term:
    preferred_term: UBA1
    term:
      id: hgnc:12469
      label: UBA1
  notes: >-
    UBA1 (ubiquitin-like modifier activating enzyme 1), the E1 ubiquitin-activating
    enzyme, on Xp11.3. Hemizygous pathogenic variants cluster in exon 15 / the
    active adenylation domain (e.g. p.Met539Ile, p.Ser547Gly, the c.1731C>T
    synonymous variant reducing expression). The synonymous allele has direct
    expression evidence. Among tested missense alleles, p.Met539Ile and
    p.Ser547Gly retained adenylation activity in vitro while p.Glu557Val showed a
    moderate reduction, so neither a uniform adenylation defect nor complete
    loss-of-function is assigned across SMAX2 variants.
  evidence:
  - reference: PMID:18179898
    reference_title: "Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "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"
    explanation: Identifies the causative UBA1 (UBE1) variants segregating with XL-SMA.
  - reference: PMID:18179898
    reference_title: "Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "XL-SMA is part of a growing list of neurodegenerative disorders associated with defects in the ubiquitin-proteasome pathway"
    explanation: Places XL-SMA among ubiquitin-proteasome pathway neurodegenerative disorders without proving one identical biochemical consequence for all variants.
  - reference: PMID:29034082
    reference_title: "Functional characterizations of rare UBA1 variants in X-linked Spinal Muscular Atrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our data revealed that only one of the three XL-SMA missense variants impairs the Ubiquitin-adenylating ability of Uba1."
    explanation: Establishes allele-specific rather than uniform adenylation impairment among the three tested missense variants.
differential_diagnoses:
- name: SMN1-Related Proximal Spinal Muscular Atrophy
  description: >-
    Severe SMN1-related SMA can present with congenital or infantile hypotonia,
    areflexia, weakness, and motor-neuron loss. It is autosomal recessive and
    caused by biallelic SMN1 disruption, whereas SMAX2 is diagnosed through a
    hemizygous UBA1 pathogenic variant in a male. Arthrogryposis and fractures are
    especially useful SMAX2 clues but are not by themselves molecular diagnoses.
  distinguishing_features:
  - X-linked recessive inheritance (affected males) and UBA1 variants favor SMAX2; autosomal recessive SMN1 disruption favors proximal SMA.
  - Prominent congenital arthrogryposis and perinatal fractures favor SMAX2.
  - Normal SMN1 in SMAX2 versus biallelic SMN1 loss in proximal SMA.
  - The unaffected thalamus in the detailed SMAX2 autopsy contrasts with reported thalamic involvement in typical SMN1-associated SMA.
  disease_term:
    preferred_term: spinal muscular atrophy
    term:
      id: MONDO:0001516
      label: spinal muscular atrophy
  evidence:
  - reference: PMID:18572081
    reference_title: "Spinal muscular atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is caused by homozygous disruption of the survival motor neuron 1 (SMN1) gene by deletion, conversion, or mutation."
    explanation: Supports the distinct SMN1 genetic basis of proximal SMA.
  - reference: PMID:23518311
    reference_title: "Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "In contrast to typical SMN1-associated SMA, the thalamus was unaffected."
    explanation: Supplies the neuropathologic discriminator stated above.
- name: Kennedy Disease
  description: >-
    Kennedy disease (X-linked spinal and bulbar muscular atrophy, SBMA) is also an
    X-linked lower motor neuron disease, but is adult-onset and caused by an
    androgen-receptor (AR) CAG trinucleotide repeat expansion, not an infantile
    exon-15 UBA1 variant, and lacks
    the congenital arthrogryposis and infantile lethality of SMAX2.
  distinguishing_features:
  - Adult midlife onset in Kennedy disease versus congenital/infantile onset in SMAX2.
  - AR CAG expansion versus an SMAX2-associated UBA1 variant.
  - Absence of congenital contractures/arthrogryposis in Kennedy disease.
  disease_term:
    preferred_term: Kennedy disease
    term:
      id: MONDO:0010735
      label: Kennedy disease
  evidence:
  - reference: PMID:20301508
    reference_title: "Spinal and Bulbar Muscular Atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of SBMA is established in a male proband by the identification of a hemizygous expansion of a CAG trinucleotide repeat (>35 CAGs) in AR by molecular genetic testing."
    explanation: Directly supports the AR CAG-repeat molecular discriminator for Kennedy disease.
  - reference: PMID:20301508
    reference_title: "Spinal and Bulbar Muscular Atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spinal and bulbar muscular atrophy (SBMA) is a gradually progressive neuromuscular disorder in which degeneration of lower motor neurons results in muscle weakness, muscle atrophy, and fasciculations in affected males."
    explanation: Supports the gradually progressive motor-neuron phenotype that contrasts with congenital SMAX2.
- name: X-Linked Distal Spinal Muscular Atrophy Type 3
  description: >-
    SMAX3 is an ATP7A-related distal hereditary motor neuropathy with progressive
    distal weakness and atrophy. It is distinguished from congenital SMAX2 by its
    ATP7A basis, distal distribution, and generally later, slower course.
  distinguishing_features:
  - Pathogenic ATP7A variants favor SMAX3; pathogenic UBA1 variants favor SMAX2.
  - Distal progressive gait and hand/foot involvement favor SMAX3 over congenital generalized weakness with arthrogryposis.
  disease_term:
    preferred_term: X-linked distal spinal muscular atrophy type 3
    term:
      id: MONDO:0010338
      label: X-linked distal spinal muscular atrophy type 3
  evidence:
  - reference: PMID:20170900
    reference_title: "Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We identified two unique ATP7A missense mutations (p.P1386S and p.T994I) in males with distal motor neuropathy in two families."
    explanation: Primary human-family evidence directly establishes the ATP7A basis of the distal motor neuropathy.
  - reference: PMID:20170900
    reference_title: "Missense mutations in the copper transporter gene ATP7A cause X-linked distal hereditary motor neuropathy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "certain missense mutations at this locus can cause a syndrome restricted to progressive distal motor neuropathy without overt signs of systemic copper deficiency."
    explanation: Directly supports the progressive distal distribution and absence of systemic copper-deficiency signs.
- name: UBA1-Related Non-Kennedy Spinal-Bulbar Muscular Atrophy
  description: >-
    A separate adult-onset X-linked spinal-bulbar phenotype has been reported in a
    family with UBA1 p.Ile500Thr. Shared gene identity does not make that adult
    phenotype SMAX2: age at onset, bulbar distribution, variant position, and lack
    of congenital arthrogryposis define an important allelic boundary.
  distinguishing_features:
  - Adult spinal-bulbar presentation versus prenatal/neonatal SMAX2 presentation.
  - UBA1 p.Ile500Thr in the reported adult pedigree versus the exon-15 variants reported in infantile SMAX2; both affect residues near the ATP-binding region, so location alone is not diagnostic.
  evidence:
  - reference: PMID:35996994
    reference_title: "Identification of UBA1 as the causative gene of an X-linked non-Kennedy spinal-bulbar muscular atrophy."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A missense mutation in UBA1 (c.T1499C; p.Ile500Thr) was identified as the probable cause of the non-Kennedy SBMA in the pedigree."
    explanation: Supports a distinct UBA1-related non-Kennedy spinal-bulbar phenotype rather than extending SMAX2 indiscriminately to adult disease.
- name: Spinal Muscular Atrophy with Respiratory Distress Type 1
  description: >-
    SMARD1 is an autosomal recessive IGHMBP2 disorder with early respiratory
    failure and motor weakness. Diaphragmatic palsy and distal-predominant weakness
    favor SMARD1; congenital arthrogryposis/fractures, X-linked segregation, and a
    hemizygous UBA1 variant favor SMAX2.
  distinguishing_features:
  - Biallelic IGHMBP2 variants and autosomal recessive inheritance favor SMARD1.
  - Early diaphragmatic palsy with distal weakness favors SMARD1.
  disease_term:
    preferred_term: spinal muscular atrophy with respiratory distress type 1
    term:
      id: MONDO:0011436
      label: autosomal recessive distal spinal muscular atrophy 1
  evidence:
  - reference: PMID:11528396
    reference_title: "Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Here we demonstrate that SMARD type 1 (SMARD1) results from mutations in the gene encoding immunoglobulin micro-binding protein 2 (IGHMBP2; on chromosome 11q13.2-q13.4)."
    explanation: Supports the distinct IGHMBP2 genetic basis of SMARD1.
  - reference: PMID:35611426
    reference_title: "Spinal muscular atrophy with respiratory distress type 1 (SMARD1): a rare cause of hypotonia, diaphragmatic weakness, and respiratory failure in infants."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The initial symptoms of patients with SMARD1 are respiratory distress and distal muscle weakness manifesting in the infantile period due to progressive degeneration of α-motor neurons."
    explanation: Directly supports early respiratory distress and distal-predominant weakness as clinical discriminators.
- name: Spinal Muscular Atrophy with Congenital Bone Fractures 2
  description: >-
    ASCC1-related SMABF2 can closely mimic SMAX2 through prenatal or neonatal
    hypotonia, congenital contractures, long-bone fractures, pulmonary hypoplasia,
    and respiratory distress. Biallelic ASCC1 variants and autosomal recessive
    inheritance favor SMABF2; a hemizygous UBA1 pathogenic variant and X-linked
    segregation favor SMAX2.
  distinguishing_features:
  - Biallelic ASCC1 variants and autosomal recessive inheritance favor SMABF2.
  - Prenatal long-bone fractures, congenital contractures, and respiratory distress overlap substantially and require molecular discrimination.
  disease_term:
    preferred_term: spinal muscular atrophy with congenital bone fractures 2
    term:
      id: MONDO:0014807
      label: spinal muscular atrophy with congenital bone fractures 2
  evidence:
  - reference: PMID:33931933
    reference_title: "Biallelic ASCC1 variants including a novel intronic variant result in expanded phenotypic spectrum of spinal muscular atrophy with congenital bone fractures 2 (SMABF2)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Spinal muscular atrophy with congenital bone fractures 2 (SMABF2), a type of arthrogryposis multiplex congenita (AMC), is characterized by congenital joint contractures, prenatal fractures of long bones, and respiratory distress and results from biallelic variants in ASCC1."
    explanation: Directly supports both the overlapping phenotype and the distinct biallelic ASCC1 etiology.
diagnosis:
- name: Supportive Clinical and Electrophysiologic Assessment
  description: >-
    No consensus clinical diagnostic criteria have been published. Congenital
    hypotonia, areflexia, weakness, contractures and/or fractures, male sex or
    X-linked segregation, EMG/NCS evidence of a neurogenic process, and negative
    SMN1 testing are supportive findings. They should prompt UBA1 testing but do
    not establish SMAX2 without a pathogenic or likely pathogenic UBA1 variant.
  diagnosis_term:
    preferred_term: electromyography procedure
    term:
      id: NCIT:C38056
      label: Electromyography
  evidence:
  - reference: PMID:32181232
    reference_title: "A Pathogenic Missense Variant (c.1617G>A, p.Met539Ile) in UBA1 Causing Infantile X-Linked Spinal Muscular Atrophy (SMAX2)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The brain MRI of the proband's showed normal results but the electromyography results showed multiple peripheral neurogenic lesions."
    explanation: Directly supports EMG as a supportive neurogenic finding rather than a disease-specific diagnostic test.
  - reference: PMID:32181232
    reference_title: "A Pathogenic Missense Variant (c.1617G>A, p.Met539Ile) in UBA1 Causing Infantile X-Linked Spinal Muscular Atrophy (SMAX2)."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "normal SMN1 molecular sequencing, and male gender in a simple case or an X-linked manner of inheritance in families with multiple patients"
    explanation: Supports normal SMN1 testing as a useful exclusionary/supportive finding in the SMAX2 workup.
- name: UBA1 Molecular Confirmation and Variant Interpretation
  description: >-
    Establish the diagnosis in an affected male by identifying a hemizygous
    pathogenic or likely pathogenic UBA1 variant in the appropriate phenotype.
    A UBA1 variant of uncertain significance neither establishes nor excludes
    SMAX2; segregation, allele-specific functional data, and periodic
    reinterpretation are needed, especially given the heterogeneous effects of
    exon-15 variants.
  diagnosis_term:
    preferred_term: molecular genetic testing
    term:
      id: NCIT:C19770
      label: Molecular Analysis
  evidence:
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The diagnosis of X-linked infantile spinal muscular atrophy is established in a male proband with suggestive clinical features and a hemizygous pathogenic variant in UBA1 identified by molecular genetic testing."
    explanation: Establishes the required clinical-plus-pathogenic-variant basis while excluding a VUS-only result from confirmation.
- name: Family Variant Testing and Recurrence Counseling
  description: >-
    Once a familial UBA1 pathogenic variant is known, test at-risk female relatives;
    prenatal and preimplantation genetic testing are possible. Counseling should
    explain that de novo variants occur, heterozygous females are usually but not
    invariably unaffected, and a negative maternal blood test does not reduce
    recurrence risk to zero because maternal germline mosaicism remains possible.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  evidence:
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Once the UBA1 pathogenic variant has been identified in an affected family member, carrier testing for at risk female relatives and prenatal and preimplantation genetic testing are possible."
    explanation: Supports cascade carrier testing and reproductive testing after variant identification.
treatments:
- name: Respiratory and Airway Support
  description: >-
    Use airway-clearance and secretion-management techniques with noninvasive
    ventilatory support when possible; permanent invasive ventilation may be
    considered according to goals of care. This is supportive treatment, not an
    SMN-directed disease-modifying therapy.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Respiratory Insufficiency
    treatment_effect: MODULATES
    description: Ventilatory and airway-clearance support mitigates the respiratory phenotype without correcting the UBA1 lesion.
  evidence:
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "provide rigorous airway clearance techniques, secretion management, and, ideally, noninvasive ventilatory support, although tracheostomy with permanent mechanical ventilation can be considered"
    explanation: Supports the respiratory management measures listed here.
- name: Nutrition and Feeding Support
  description: Ensure adequate calories with supplementation and/or gastrostomy feeding when needed; monitor swallowing, reflux, constipation, and aspiration risk.
  treatment_term:
    preferred_term: Nutritional Support
    term:
      id: NCIT:C15433
      label: Nutritional Support
  target_mechanisms:
  - target: Poor Suck
    treatment_effect: MODULATES
    description: Nutritional assessment and enteral support mitigate consequences of impaired sucking and swallowing.
  evidence:
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Assure adequate caloric intake by caloric supplementation and/or gastrostomy feedings"
    explanation: Supports active nutritional assessment and enteral support when needed.
- name: Orthopedic and Rehabilitation Care
  description: Orthopedic follow-up plus physical and occupational therapy for contractures and progressive scoliosis.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: physical therapy
    term:
      id: NCIT:C15302
      label: Physical Therapy
  target_mechanisms:
  - target: Arthrogryposis Multiplex Congenita
    treatment_effect: MODULATES
    description: Physical and occupational therapy manage the fixed contractures of arthrogryposis without correcting the UBA1 lesion.
  - target: Scoliosis
    treatment_effect: MODULATES
    description: Orthopedic follow-up with physical and occupational therapy manages progressive spinal curvature without correcting the UBA1 lesion.
  evidence:
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Orthopedic consultation and physical and occupational therapy to manage contractures and progressive scoliosis."
    explanation: Supports multidisciplinary orthopedic and rehabilitation management.
- name: Orthopedic surveillance and specialist management
  action_category: MONITORING
  description: >-
    Arrange orthopedic consultation and longitudinal assessment of contractures
    and progressive spinal curvature, distinct from the rehabilitative therapy itself.
  treatment_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Orthopedic consultation and physical and occupational therapy to manage contractures and progressive scoliosis."
    explanation: GeneReviews explicitly recommends orthopedic consultation in addition to therapy.
- name: Gastroesophageal reflux management
  description: Apply standard clinical treatment for gastroesophageal reflux disease.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Gastroesophageal Reflux
    treatment_effect: MODULATES
    description: Symptomatic reflux management mitigates the manifestation without altering UBA1 dysfunction.
  evidence:
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Standard treatment for gastroesophageal reflux disease."
    explanation: Directly states the GeneReviews management recommendation.
- name: Constipation management
  description: Manage constipation with dietary measures or medication as clinically indicated.
  treatment_term:
    preferred_term: supportive care
    term:
      id: NCIT:C15747
      label: Supportive Care
  target_mechanisms:
  - target: Constipation
    treatment_effect: MODULATES
    description: Diet or medication mitigates constipation without altering the underlying neuromuscular disorder.
  evidence:
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "manage constipation with diet or medication"
    explanation: Directly states the GeneReviews management recommendation.
- name: Early multidisciplinary surveillance
  action_category: MONITORING
  description: >-
    Follow affected children at least monthly while severity and disease course
    are being established, coordinating neurology, respiratory, orthopedic,
    rehabilitation, nutrition, and gastrointestinal care.
  treatment_term:
    preferred_term: clinical assessment
    term:
      id: NCIT:C124351
      label: Clinical Evaluation
  evidence:
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Affected children should be followed at least monthly until the severity and disease course are more clearly delineated."
    explanation: Directly states the recommended early surveillance interval.
- name: Genetic Counseling
  description: Counsel families about X-linked transmission, the possibility of de novo variants, testing of at-risk relatives, and reproductive options.
  treatment_term:
    preferred_term: Genetic Counseling
    term:
      id: NCIT:C15240
      label: Genetic Counseling
  evidence:
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Heterozygous females have a 50% chance of transmitting the pathogenic variant with each pregnancy."
    explanation: Supports counseling about recurrence risk for a heterozygous female.
discussions:
- discussion_id: gap_smax2_human_model_allele_and_tissue_mismatch
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  prompt: >-
    Do generic UBA1 knockdown models reproduce the allele-specific human SMAX2
    mechanism in motor neurons, sensory neurons, cerebellar cells, and skeletal
    muscle, given that p.Met539Ile and p.Ser547Gly retain adenylation activity
    whereas p.Glu557Val does not?
  rationale: >-
    Muscle-targeted UBA1 knockdown in Drosophila and mice reduces ubiquitination
    and muscle function, but it does not model a specific human exon-15 allele.
    Human biochemical assays show heterogeneous effects across missense variants,
    and patient tissue establishes motor, sensory, and cerebellar pathology without
    demonstrating reduced ubiquitination. The model result is therefore evidence
    for a testable muscle-autonomous route, not proof of the human mechanism.
  attaches_to:
  - pathophysiology#Allele-Specific UBA1 Dysfunction
  - pathophysiology#Candidate UBA1-Dependent Cellular Dysregulation
  - pathophysiology#Anterior Horn Motor Neuron Degeneration
  - pathophysiology#Sensory Neuron and Tract Pathology
  - pathophysiology#Skeletal Muscle-Autonomous Dysfunction
  proposed_experiments:
  - experiment_id: exp_smax2_isogenic_allele_tissue_panel
    name: Isogenic human SMAX2 allele-by-cell-type panel
    description: >-
      Introduce p.Met539Ile, p.Ser547Gly, p.Glu557Val, and c.1731C>T separately
      into one human iPSC background, differentiate matched motor neurons, sensory
      neurons, and skeletal muscle fibers, and compare them with corrected
      patient-derived lines and wild-type controls.
    experiment_type:
      preferred_term: isogenic iPSC allele-by-cell-type experiment
    model_systems:
    - name: Isogenic human iPSC-derived motor, sensory, and skeletal-muscle models
      description: Allele-matched human cultures tested separately and in motor-unit co-culture.
      experimental_model_type: IPSC_DERIVED_MODEL
      organism:
        preferred_term: human
        term:
          id: NCBITaxon:9606
          label: Homo sapiens
      cell_types:
      - preferred_term: motor neuron
        term:
          id: CL:0000100
          label: motor neuron
      - preferred_term: sensory neuron
        term:
          id: CL:0000101
          label: sensory neuron
      - preferred_term: skeletal muscle fiber
        term:
          id: CL:0008002
          label: skeletal muscle fiber
    readouts:
    - name: Allele-specific UBA1 reaction kinetics and ubiquitin conjugation
      target: pathophysiology#Allele-Specific UBA1 Dysfunction
      description: Measure adenylation, thioester formation, E2 transfer, global and substrate-specific ubiquitination, and proteasome flux in each cell type.
    - name: Cell-type injury and function
      target: pathophysiology#Candidate UBA1-Dependent Cellular Dysregulation
      description: Measure neuronal survival and axonal integrity, neuromuscular-junction formation, muscle contractility, and transcript splicing.
    decision_criterion: >-
      A human mechanism is supported only if an allele-specific molecular defect
      reproducibly precedes injury in the clinically implicated cell type; failure
      of knockdown-like ubiquitination changes in p.Met539Ile or p.Ser547Gly would
      refute a uniform adenylation/ubiquitination-deficiency model.
    would_support:
    - pathophysiology#Allele-Specific UBA1 Dysfunction
    - pathophysiology#Candidate UBA1-Dependent Cellular Dysregulation
    would_refute:
    - pathophysiology#Skeletal Muscle-Autonomous Dysfunction
  - experiment_id: exp_smax2_patient_tissue_ubiquitinome
    name: Genotype-resolved human SMAX2 multi-tissue profiling
    description: >-
      Prospectively collect fibroblasts, blood, clinically obtained muscle, and
      postmortem nervous tissue across severe and mild SMAX2 alleles, with matched
      neurologic disease and unaffected controls, and profile UBA1 isoforms,
      splicing, binding partners, ubiquitin conjugates, proteasome flux, and
      tissue pathology.
    experiment_type:
      preferred_term: genotype-resolved human multi-tissue study
    model_systems:
    - name: Human SMAX2 patient tissues and primary cultures
      description: Patient material stratified by UBA1 allele and clinical severity.
      experimental_model_type: PRIMARY_CELL_CULTURE
      organism:
        preferred_term: human
        term:
          id: NCBITaxon:9606
          label: Homo sapiens
    readouts:
    - name: Tissue-specific UBA1 mechanism
      target: pathophysiology#Candidate UBA1-Dependent Cellular Dysregulation
      description: Identify whether altered splicing, binding partners, ubiquitination, or proteasome flux co-segregates with tissue injury and allele severity.
    decision_criterion: >-
      Concordant allele- and tissue-specific molecular changes in human material
      must match the affected motor, sensory, cerebellar, or muscle compartment
      before an animal-knockdown mechanism is promoted to a human causal claim.
    would_support:
    - pathophysiology#Anterior Horn Motor Neuron Degeneration
    - pathophysiology#Sensory Neuron and Tract Pathology
    - pathophysiology#Cerebellar Developmental and Degenerative Abnormalities
    - pathophysiology#Skeletal Muscle-Autonomous Dysfunction
  evidence:
  - reference: PMID:42402962
    reference_title: "UBA1 knockdown dysregulates the levels of UBA1-sensitive proteins and impairs muscle function in Drosophila and mice."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: "However, it remains unexplored how UBA1 impacts the muscle proteome, and whether muscle weakness can arise from reducing UBA1 function solely in skeletal muscle."
    explanation: States the motivating tissue-mechanism question addressed in models but not yet resolved in human SMAX2.
  - reference: PMID:29034082
    reference_title: "Functional characterizations of rare UBA1 variants in X-linked Spinal Muscular Atrophy."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Our data revealed that only one of the three XL-SMA missense variants impairs the Ubiquitin-adenylating ability of Uba1."
    explanation: The allele-specific biochemical result establishes why generic UBA1 knockdown cannot be assumed to model every human SMAX2 allele.
- discussion_id: gap_smax2_sex_specific_ascertainment_and_prevalence
  kind: KNOWLEDGE_GAP
  status: OPEN
  prompt: >-
    What are genotype-specific birth prevalence, survival, and penetrance in
    heterozygous females, including the role of X-inactivation and de novo variants?
  rationale: >-
    Reports are dominated by severely affected hemizygous male probands and
    multiplex families, while GeneReviews states that heterozygous females are
    usually unaffected and a recent case was de novo. This design cannot provide an
    unbiased female penetrance estimate, sex-specific rate, or genotype-specific
    natural history.
  attaches_to:
  - pathophysiology#Allele-Specific UBA1 Dysfunction
  evidence:
  - reference: PMID:20301739
    reference_title: "Spinal Muscular Atrophy, X-Linked Infantile."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "females who inherit the pathogenic variant will be heterozygotes and will usually not be affected."
    explanation: The qualifier "usually" leaves female penetrance and modifiers unresolved.
📚

References & Deep Research

References

4
PMID:17224690
X-linked infantile spinal muscular atrophy: clinical definition and molecular mapping.
No top-level findings curated for this source.
PMID:18179898
Rare missense and synonymous variants in UBE1 are associated with X-linked infantile spinal muscular atrophy.
No top-level findings curated for this source.
PMID:23518311
Clinical and neuropathological features of X-linked spinal muscular atrophy (SMAX2) associated with a novel mutation in the UBA1 gene.
No top-level findings curated for this source.
PMID:20301739
Spinal Muscular Atrophy, X-Linked Infantile.
No top-level findings curated for this source.