cardiomyopathy-hypotonia-lactic acidosis syndrome

Cardiomyopathy-hypotonia-lactic acidosis syndrome is an ultra-rare inherited metabolic condition that primarily affects the heart and skeletal muscles in the newborn period. It results from harmful changes in the SLC25A3 gene, which encodes a mitochondrial phosphate carrier needed for energy production inside cells. Infants typically present at or shortly after birth, and both boys and girls can be affected. Because fewer than 1 in 1 million people are thought to have this condition, most clinicians encounter it only through case reports. Severity and symptoms vary widely between individuals, even within the same family.

The earliest signs often appear in the first hours or days of life. Newborns may be noticeably floppy because of marked muscle hypotonia and can develop rapid breathing or bluish skin from lactic and metabolic acidosis. Hypertrophic cardiomyopathy—thickening of the heart muscle—can lead to low-output heart failure and cyanosis. Feeding difficulties and poor weight gain are common, and some infants experience respiratory distress that requires supportive ventilation. Less frequently, progressive muscle weakness or myopathy becomes evident as the child grows. Not all individuals experience all features, and severity varies considerably.

The syndrome is caused by autosomal recessive variants in the SLC25A3 gene. This gene makes a transporter that shuttles phosphate into mitochondria so cells can generate ATP, the body’s main energy currency. When both copies of the gene are altered, energy production falters, especially in tissues with high energy demands such as heart muscle and skeletal muscle, leading to cardiomyopathy, hypotonia, and lactic acidosis. Autosomal recessive inheritance means an individual must receive one altered copy of SLC25A3 from each parent to be affected; carrier parents are usually healthy but have a 25 percent chance with each pregnancy of having an affected child. This condition is more common when parents share a common ancestor because related individuals are more likely to carry the same rare genetic variant. Genetic counseling is strongly recommended for families to discuss carrier testing and reproductive options.

Currently, management focuses on supportive care tailored to each individual’s needs. Cardiac complications may be addressed with medications that improve heart function, careful fluid management, and, in severe cases, evaluation for advanced cardiac support. Metabolic acidosis is treated with prompt correction of acid-base disturbances and optimization of respiratory status. Nutritional support, physical therapy, and, when necessary, assisted ventilation help maintain growth and comfort. Because multiple organ systems can be involved, long-term care should be coordinated by a multidisciplinary team that includes cardiologists, metabolic specialists, neurologists, dietitians, and palliative care professionals. Regular surveillance is essential to detect evolving cardiac dysfunction, monitor growth and nutritional status, and manage emerging metabolic crises before they become serious. Families should discuss all treatment options and surveillance plans with their healthcare team to determine what is most appropriate for their situation.

Only a few individuals with cardiomyopathy-hypotonia-lactic acidosis syndrome have been described, so understanding of long-term outcomes continues to evolve. Historically, reported infants experienced severe complications within the first year of life, but outcomes may differ for children diagnosed early and managed in modern intensive-care settings. Some babies respond well to aggressive metabolic and cardiac management, while others progress despite intervention. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with genetic counselors and specialists familiar with mitochondrial disorders to better understand prognosis, plan care, and explore supportive resources.