What are the effects and treatment options of a DARS1 (Aspartyl-tRNA synthetase 1) mutation in children?

DARS1 Mutation in Children

DARS1 mutations cause a rare leukodystrophy called Hypomyelination with Brainstem and Spinal Cord involvement and Leg Spasticity (HBSL), characterized by developmental delay or regression, progressive lower extremity spasticity, and distinctive white matter abnormalities on brain MRI, with no established curative treatment currently available. 1, 2, 3

Clinical Manifestations

Motor and Developmental Features

• Disease onset typically occurs during early childhood (ranging from 4 months to 18 years), with initial symptoms of developmental delay or regression 4, 3
• Progressive lower extremity spasticity is the hallmark motor finding, often accompanied by active tendon reflexes and positive Babinski sign 2, 4
• Patients experience regression of previously acquired motor milestones, with variable severity—some children may only achieve standing with assistance by age 8, while others may eventually walk independently by age 9 2, 4
• Ataxia, seizures, and nystagmus can occur as part of the clinical spectrum 5

Cognitive and Neurological Features

• Cognitive development is typically preserved or only mildly affected, distinguishing HBSL from many other leukodystrophies 2, 4
• Intellectual disabilities may occur in some patients, representing the more severe end of the spectrum 5
• Clinical phenotypes vary significantly across different age groups and mutation types 4

Diagnostic Imaging Characteristics

Brain MRI Findings

• Characteristic pattern shows high T2-weighted signal and slightly low T1-weighted signal in bilateral deep cerebral white matter, consistent with hypomyelination 2, 4
• Lesions may extend to involve subcortical white matter, corpus callosum, and internal capsule in more extensive cases 4
• No abnormal diffusion-weighted imaging (DWI) signal is typically present 4
• The brainstem may show involvement, though this is variable 1, 3

Spinal Cord Imaging

• Spinal MRI may show abnormal signals in the cervical cord, though some patients demonstrate no spinal abnormalities 2, 4

Genetic Basis and Molecular Pathology

Gene Function

• DARS1 encodes cytoplasmic aspartyl-tRNA synthetase, an essential enzyme for protein synthesis 3
• Mutations cause nonsynonymous changes to highly conserved amino acids in the C-terminal lobe adjacent to or within the active-site pocket 3
• The mutations are inherited in an autosomal recessive pattern, requiring compound heterozygous or homozygous mutations for disease manifestation 2, 4, 3

Identified Mutations

• Multiple pathogenic mutations have been identified, including novel variants such as c.1498_1499insTCA (p.500_501insIle), c.1210A>G (p.Met404Val), c.1432A>G (p.Met478Val), c.1363T>C, and c.821C>G 2, 4
• Five of the affected amino acids are unchanged between yeast and humans, highlighting their critical functional importance 3

Relationship to Similar Disorders

• HBSL bears striking resemblance to LBSL (Leukoencephalopathy with Brain stem and Spinal cord involvement and elevated Lactate), which is caused by mutations in the mitochondria-specific DARS2 gene 3
• This similarity suggests a common underlying molecular pathology between cytoplasmic and mitochondrial aspartyl-tRNA synthetase deficiencies 3

Systemic Manifestations Beyond the Nervous System

Metabolic and Peripheral Effects

• Animal models reveal that DARS1 mutations affect energy metabolism and peripheral organs, including reduced body fat, increased respiratory exchange ratio, reduced liver steatosis, and bone marrow hypocellularity 5
• These metabolic and peripheral changes may be overlooked in patients with severe neurological deficits but should be included in differential diagnosis 5
• Developmental delay manifests systemically with reduced body weight and size 5

Diagnostic Approach

Genetic Testing Strategy

• Targeted next-generation sequencing, whole-exome sequencing, and Sanger sequencing should be employed to identify DARS1 mutations in suspected cases 2, 4
• Testing should include both the patient and parents to confirm inheritance pattern 4
• Genetic counseling is essential given the autosomal recessive inheritance 4

Clinical Evaluation

• Look specifically for the triad of developmental delay/regression, progressive lower extremity spasticity with hyperreflexia, and preserved or mildly impaired cognition 2, 4
• Brain MRI showing hypomyelination pattern in deep white matter with characteristic T1/T2 signal changes is highly suggestive 2, 4
• Consider metabolic screening given the systemic effects demonstrated in animal models 5

Treatment and Management

Current Therapeutic Options

• No curative treatment is currently available for HBSL 1
• Management is primarily supportive and symptomatic 1
• Physical therapy and spasticity management are key components of care given the progressive lower extremity involvement 2, 4

Prognosis

• The disease represents a spectrum disorder with variable severity 5
• Some patients achieve limited motor milestones while others may progress to independent ambulation, though with significant delay 2, 4
• Nearly half of children with leukoencephalopathies remain without specific diagnosis, making genetic testing particularly valuable 3

Important Clinical Pitfalls

• Do not confuse HBSL with LBSL—while clinically similar, HBSL is caused by cytoplasmic DARS1 mutations whereas LBSL results from mitochondrial DARS2 mutations 3
• The preservation of cognitive function distinguishes HBSL from many other leukodystrophies and should not delay consideration of this diagnosis 2, 4
• Normal spinal MRI does not exclude HBSL, as spinal involvement is variable 2, 4
• Metabolic and peripheral manifestations may be subtle but should be assessed as part of comprehensive evaluation 5