HMG-CoA lyase deficiency

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What is HMG-CoA Lyase Deficiency?

HMG-CoA lyase deficiency, caused by harmful genetic changes (mutations) in the HMGCL gene, is an inherited metabolic disease that prevents the body from breaking down the amino acid leucine. Individuals with HMG-CoA lyase deficiency are also unable to produce ketones, a key source of energy used by the body during times of fasting or illness. These deficiencies lead to a build-up of toxic substances in the body, which cause the symptoms of the disease.

In most children, symptoms of HMG-CoA lyase deficiency appear before one year of age. In approximately 30% of affected individuals, symptoms begin between the second and fifth day of life. A few cases of late-onset disease, in which the disease appears during puberty or adulthood, have been reported. The first symptoms are low blood sugar, vomiting, lack of energy, difficulty feeding, irritability, and poor muscle tone that causes the body to seem floppy. The symptoms often appear quickly and are known as a "metabolic crisis." These episodes, or crises, may be triggered by illness, infection, periods of fasting, or stress. Consumption of large amounts of protein may also serve as a catalyst for metabolic crisis. If unrecognized and untreated with a special diet, the episodes can rapidly progress to permanent neurological damage, coma, and even death. Even when appropriately treated, individuals with HMG-CoA lyase deficiency are at increased risk for infections and pancreatitis, which may be fatal.

How common is HMG-CoA Lyase Deficiency?

HMG-CoA lyase deficiency has been reported in at least 150 individuals worldwide, but the global incidence is unknown. Note that less severe presentations of HMG-CoA lyase deficiency may not be recognized. It is more common among individuals of certain ethnic groups, most notably those of Saudi Arabian, Portuguese, and Spanish ancestry. However, estimates of incidence in these populations have not been published.

How is HMG-CoA Lyase Deficiency treated?

A physician specializing in metabolic diseases should help construct a treatment plan for any child with HMG-CoA lyase deficiency. Often these plans include avoidance of fasting, feeding with a low-leucine diet, medications, and prompt attention during metabolic crises. Diets will need to be carefully structured both to avoid problem foods and to ensure proper nutrition. In some cases, meals may be necessary around the clock, even overnight. A specialist will also devise a "sick-day plan" to use when a child shows signs of illness that could lead to a metabolic crisis. This typically involves frequent meals with carbohydrates and increased fluid intake, even if the child is not hungry or thirsty. During times of illness, fats and proteins should be completely eliminated from the diet.

As children get older, the disease frequently becomes easier to manage, and the risk of metabolic crisis decreases. However, many will still need lifelong dietary treatment. It is believed that those who receive treatment before their first metabolic crisis do better in the long term.

What is the prognosis for an individual with HMG-CoA Lyase Deficiency?

Prompt and careful management of symptoms is important to help reduce the long-term effects of the condition. Even with appropriate care, many individuals will experience some type of intellectual or learning disability and disordered movement. This condition can be fatal in approximately 20% of cases. Among those that survive their first incident, repeated crises may result in brain damage and significant learning and intellectual disabilities. After childhood, symptoms are often milder, but long-term effects may include recurrent seizures, muscle weakness, heart damage, vision loss, hearing loss, and intellectual disability.