LARS Syndrome, also known as Leukodystrophy with Biotin-responsive Basal Ganglia Disease, is a rare, inherited neurological disorder. It is a progressive condition that affects the central nervous system, resulting in a wide spectrum of severity. The duration of LARS Syndrome is highly variable, ranging from a life-limiting infantile presentation to a more slowly progressing course that allows survival into later childhood or adolescence. The severity of the underlying genetic change dictates the speed of the disease’s progression and the individual’s long-term outlook.
The Genetic Basis and Classification of LARS Syndrome
LARS Syndrome is classified as a mitochondrial disorder, affecting the energy-producing centers of the body’s cells. The cause is a mutation in the LARS2 gene, which instructs the creation of the mitochondrial leucyl-tRNA synthetase enzyme. This enzyme attaches the amino acid leucine to its transfer RNA (tRNA) inside the mitochondria, a fundamental step in protein synthesis necessary for cellular respiration. A defect in the LARS2 enzyme impairs the assembly of mitochondrial protein complexes, leading to functional failure that especially impacts high-energy tissues like the brain and nervous system.
The resulting clinical picture is highly diverse, known as a broad phenotypic spectrum. The most severe presentation is lethal infantile multisystem failure, characterized by hydrops, lactic acidosis, and sideroblastic anemia (HLASA). Less severe mutations are often associated with Perrault syndrome, which includes hearing loss and ovarian failure, alongside progressive neurological issues and leukodystrophy. The severity of the genetic mutation correlates directly with residual enzyme activity, determining the age of symptom onset and the pace of the disease.
Stages of Symptom Onset and Disease Progression
The onset of LARS Syndrome typically occurs in infancy or early childhood, depending on the specific genetic variants inherited. Initial symptoms are neurological, often presenting as developmental delay, where children fail to meet motor and cognitive milestones. Generalized hypotonia, or low muscle tone, is also a frequent early sign, making the infant appear “floppy.”
As the disorder progresses, neurological decline dominates the clinical picture. Brain imaging reveals leukodystrophy, the progressive destruction of the white matter necessary for rapid signal transmission. This demyelination leads to severe motor symptoms, such as spasticity, where muscles become stiff and movements are difficult to control.
Many individuals also develop movement disorders, including dystonia, characterized by involuntary muscle contractions. The disorder commonly affects sensory organs, resulting in sensorineural hearing loss and vision impairment. The timeline of this decline is highly variable, ranging from rapid deterioration in the first year of life to a more gradual neuroregression extending over several years.
Factors Determining Long-Term Outlook and Lifespan
Longevity in LARS Syndrome is highly dependent on the severity of the LARS2 gene mutation. In the most severe cases, particularly those presenting with the HLASA phenotype, the disorder is rapidly fatal, resulting in death within the first few days or months of life due to acute multisystem failure.
The immediate cause of death in these severe infantile cases is often related to complications such as pulmonary hypertension, severe lactic acidosis, and impaired cardiac or renal function. For individuals with a milder phenotype, the disease duration is extended, sometimes allowing survival into late childhood or adolescence.
In these longer-surviving forms, the gradual neurological decline and accumulation of secondary medical problems limit the lifespan. Common life-limiting complications include recurrent respiratory infections, such as pneumonia, due to diminished mobility and difficulties with swallowing. Respiratory failure may also occur due to progressive weakness of the muscles needed for breathing.
Current Management and Supportive Care Strategies
While LARS Syndrome is not curable, current management focuses on slowing the progression of the disease and addressing the complex array of symptoms. The disorder is sometimes named to reflect other metabolic conditions, such as Biotin-responsive Basal Ganglia Disease. High-dose biotin therapy is sometimes empirically trialed as a supportive measure in some mitochondrial disorders, though its efficacy in LARS2-related disorder is not universally established.
The primary strategy involves a comprehensive, multidisciplinary approach to supportive care that spans the patient’s lifetime. Physical therapy and occupational therapy are implemented early to combat muscle weakness and spasticity, helping to maintain mobility and function for as long as possible. Medications are used to manage specific symptoms, such as spasticity and movement disorders like dystonia.
Nutritional support is a major focus, often involving specialized diets or feeding tubes to ensure adequate caloric intake as swallowing difficulties emerge. Regular monitoring for hearing and vision loss allows for the timely use of hearing aids or other assistive devices. This proactive and continuous supportive care is essential for enhancing the patient’s quality of life throughout the entire duration of the disease.