Novel UBA1 Variant Associated with Attenuated X-linked SMA Phenotype
Clinical Genetics and Therapeutics
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Primary Categories:
- Clinical Genetics
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Secondary Categories:
- Clinical Genetics
Introduction
Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder characterized by progressive loss of lower motor neurons. The most common form, autosomal recessive SMA (AR-SMA), is caused by biallelic SMN1 pathogenic variants. In contrast, X-linked SMA (XL-SMA) results from pathogenic variants in UBA1. Similar to severe forms of AR-SMA, XL-SMA typically presents with progressive muscle weakness, areflexia, joint contractures, and respiratory and feeding difficulties, resulting in death prior to 2 years of life from respiratory failure. Here we present a case with atypical, attenuated presentation of XL-SMA.
Case Presentation
A male infant was born at 37 weeks gestation, as the first live child of non-consanguineous, 35-year-old, Hispanic parents. An ultrasound obtained 12 days prior to delivery showed no abnormalities. He was delivered via repeat c-section with notable findings of thick meconium-stained fluid. Initial resuscitation included bagging and deep suction. Infant required oxygen via nasal canula due to transient tachypnea of the newborn. He took all feeds by mouth but benefited from therapy for poor feeding skills. The initial physical exam was significant for bilateral hip laxity, generalized hypotonia, ulnar deviation of the hands bilaterally, and dolichocephaly. He required a Pavlik harness for 35 days due to subluxation of the left hip.
Diagnostic Workup
Motor developmental delay and generalized hypotonia persisted, and he was noted to have doughy muscles and poor proximal stability. His newborn screens and chromosomal microarray sent by the NICU were normal. Electromyography (EMG) results at 12 months suggested mild chronic neurogenic process with abnormal motor unit potentials suggestive of lower motor neuron disease. Whole exome sequencing (WES) identified a maternally inherited hemizygous UBA1 variant of uncertain significance (VUS), c.2251 C>T p.(P751S), located in exon 19. The patient’s 35-year-old maternal uncle harbors the same variant and reports minimal neuromuscular symptoms including infrequent twitching in his arms and occasional choking while drinking water, suggesting a potentially milder neuromuscular phenotype associated with this variant.
Treatment and Management
The patient benefits from therapies and has not shown regression.
Outcome and Follow-Up
At 18 months of age, he can cruise with support and eat table food without issues.
Discussion
XL-SMA typically results in death within the first 2 years of life. Diagnosis can be supported by findings of neurogenic atrophy on muscle biopsy and denervation on EMG. A definitive diagnosis is made by confirming a pathogenic variant in UBA1. Our patient exhibits hypotonia, areflexia, and abnormal EMG indicative of chronic neurogenic process affecting the proximal motor axis. WES showed a hemizygous maternally inherited UBA1 variant. The patient's maternal uncle, who harbors the same variant, exhibits only mild symptoms. However, given the patient’s physical findings and EMG abnormalities, we propose that both individuals may represent attenuated cases of XL-SMA associated with this novel UBA1 variant.
UBA1 plays a central role in the ubiquitin-proteasome system and autophagy, critical for protein homeostasis, cell cycle regulation, and DNA repair. While most pathogenic UBA1 variants cluster in exon 15, our patient presents a unique variant further downstream, in exon 19. The implications of alterations in this domain on XL-SMA function remain unclear, as no other reported patients with these specific variations are found in the literature. We propose that a disruption in this domain could alter protein function without complete inactivation, possibly explaining the milder presentation observed.
Conclusion
This report describes a patient and his maternal uncle with a novel UBA1 variant, which may suggest a newly characterized, attenuated form of XL-SMA. The patient's clinical presentation and EMG findings are consistent with SMA. Further studies are needed to evaluate similar UBA1 variants to determine if they represent an expanded phenotype of XL-SMA.
Spinal muscular atrophy (SMA) is a genetic neuromuscular disorder characterized by progressive loss of lower motor neurons. The most common form, autosomal recessive SMA (AR-SMA), is caused by biallelic SMN1 pathogenic variants. In contrast, X-linked SMA (XL-SMA) results from pathogenic variants in UBA1. Similar to severe forms of AR-SMA, XL-SMA typically presents with progressive muscle weakness, areflexia, joint contractures, and respiratory and feeding difficulties, resulting in death prior to 2 years of life from respiratory failure. Here we present a case with atypical, attenuated presentation of XL-SMA.
Case Presentation
A male infant was born at 37 weeks gestation, as the first live child of non-consanguineous, 35-year-old, Hispanic parents. An ultrasound obtained 12 days prior to delivery showed no abnormalities. He was delivered via repeat c-section with notable findings of thick meconium-stained fluid. Initial resuscitation included bagging and deep suction. Infant required oxygen via nasal canula due to transient tachypnea of the newborn. He took all feeds by mouth but benefited from therapy for poor feeding skills. The initial physical exam was significant for bilateral hip laxity, generalized hypotonia, ulnar deviation of the hands bilaterally, and dolichocephaly. He required a Pavlik harness for 35 days due to subluxation of the left hip.
Diagnostic Workup
Motor developmental delay and generalized hypotonia persisted, and he was noted to have doughy muscles and poor proximal stability. His newborn screens and chromosomal microarray sent by the NICU were normal. Electromyography (EMG) results at 12 months suggested mild chronic neurogenic process with abnormal motor unit potentials suggestive of lower motor neuron disease. Whole exome sequencing (WES) identified a maternally inherited hemizygous UBA1 variant of uncertain significance (VUS), c.2251 C>T p.(P751S), located in exon 19. The patient’s 35-year-old maternal uncle harbors the same variant and reports minimal neuromuscular symptoms including infrequent twitching in his arms and occasional choking while drinking water, suggesting a potentially milder neuromuscular phenotype associated with this variant.
Treatment and Management
The patient benefits from therapies and has not shown regression.
Outcome and Follow-Up
At 18 months of age, he can cruise with support and eat table food without issues.
Discussion
XL-SMA typically results in death within the first 2 years of life. Diagnosis can be supported by findings of neurogenic atrophy on muscle biopsy and denervation on EMG. A definitive diagnosis is made by confirming a pathogenic variant in UBA1. Our patient exhibits hypotonia, areflexia, and abnormal EMG indicative of chronic neurogenic process affecting the proximal motor axis. WES showed a hemizygous maternally inherited UBA1 variant. The patient's maternal uncle, who harbors the same variant, exhibits only mild symptoms. However, given the patient’s physical findings and EMG abnormalities, we propose that both individuals may represent attenuated cases of XL-SMA associated with this novel UBA1 variant.
UBA1 plays a central role in the ubiquitin-proteasome system and autophagy, critical for protein homeostasis, cell cycle regulation, and DNA repair. While most pathogenic UBA1 variants cluster in exon 15, our patient presents a unique variant further downstream, in exon 19. The implications of alterations in this domain on XL-SMA function remain unclear, as no other reported patients with these specific variations are found in the literature. We propose that a disruption in this domain could alter protein function without complete inactivation, possibly explaining the milder presentation observed.
Conclusion
This report describes a patient and his maternal uncle with a novel UBA1 variant, which may suggest a newly characterized, attenuated form of XL-SMA. The patient's clinical presentation and EMG findings are consistent with SMA. Further studies are needed to evaluate similar UBA1 variants to determine if they represent an expanded phenotype of XL-SMA.