What we thought for many years was developmental delay, turned out to be a rare disease…

Xiaowen (pseudonym), 6 years old, has been suffering from delayed motor, language and cognitive development since childhood and has been studying in a rehabilitation institution. Not long ago, her family discovered that Xiaowen's walking was not as steady as before, so her parents quickly took Xiaowen to Qingdao Women's and Children's Hospital for treatment.

After carefully inquiring about the patient's medical history, conducting a detailed physical examination, and reviewing the patient's previous examination data, the rehabilitation experts believed that Xiaowen did not have a simple developmental disorder, and that there might be metabolic diseases or neurodegenerative diseases as the cause. They then arranged for Xiaowen to undergo a series of examinations, and finally diagnosed him with methylmalonic acidemia combined with homocystinemia. Before specific treatment began, Xiaowen developed a fever, and his condition took a sharp turn for the worse under the attack of infection. He developed status epilepticus, coma, and a complete regression of motor language. He could not swallow independently. Through multidisciplinary cooperation between the intensive care unit, the endocrinology department, and the rehabilitation department, and with a clear etiology diagnosis and targeted treatment, the child gained a ray of hope. At present, the child's epilepsy is under control, metabolic indicators are stable, and after effective rehabilitation treatment, his cognitive and motor abilities have been greatly restored.

Methylmalonic acidemia (MMA), also known as methylmalonic aciduria, is a rare disease, an autosomal recessive genetic disease, first reported by Oberholzer et al. in 1967 and first reported in my country in 2000. It is the most common disease among organic acid metabolic diseases in my country and relatively "common" among rare diseases. The incidence and types of MMA vary greatly in different countries and regions, with an incidence of about 1/50,000 in Japan, about 1/169,000 in Germany, about 1/86,000 in Taiwan, 1/64,708 in Zhejiang Province, about 1/26,000 in Beijing and Shanghai, and 1/16,883 in Xuzhou.

The clinical manifestations of children with methylmalonic acidemia are complex and varied. The early-onset disease occurs within 1 year of age, while the late-onset disease occurs after 1 year of age. The first attack or worsening of symptoms is often followed by a "triggering event", such as infection, hunger, fatigue, high-protein diet/drugs, etc. One-third of the early-onset disease occurs in the neonatal period, with the main manifestations of vomiting, feeding difficulties, impaired consciousness, physical retardation, intellectual and motor retardation, decreased muscle tone, epilepsy, etc. In severe cases, dyspnea, anemia, hematopoiesis, coma, etc. may occur, and the mortality rate is very high. The late-onset disease can occur from infancy to adulthood, and can lead to intellectual and motor retardation, epilepsy, and hydrocephalus. Some children have other organ damage, such as renal insufficiency, renal tubular acidosis, recurrent pancreatitis, visual impairment, cardiomyopathy, bone marrow suppression, etc. In severe cases, acute metabolic decompensation or even death may occur.

The diagnosis of methylmalonic acidemia mainly relies on vitamin B12 loading test, blood amino acid, acylcarnitine spectrum analysis and total homocysteine ​​determination, urine organic acid determination, genetic analysis, etc.

Methylmalonic acidemia is preventable and treatable. Treatments include vitamin B12, betaine, L-carnitine, and a special diet that restricts propionic acid precursor amino acids, based on clinical classification and the results of a vitamin B12 loading test. Functional rehabilitation can be performed when metabolic indicators are under stable control to promote cognitive, language, and motor development.

February 28, 2023 is the 16th "International Rare Disease Day". This year's theme is "Light up your life", which aims to raise public awareness of rare diseases, help patients with rare diseases to get timely diagnosis and intervention, and improve their quality of life. Rare neurological diseases are most common with delayed motor and/or cognitive development. Therefore, it is recommended that children with delayed cognitive and motor development visit rehabilitation specialists for comprehensive evaluation and etiological examinations, early identification, timely treatment, and strive to improve prognosis and quality of life.

Author: Zhang Leihong Qingdao Women and Children's Hospital

Reviewer: Yuan Aiyun, Deputy Director of the Rehabilitation Department of Qingdao Women and Children's Hospital, Member of the Science Popularization Working Committee of the Chinese Rehabilitation Medicine Association

The popular science content of this platform has been funded by the China Association for Science and Technology's Science Popularization Department's 2022 National Science Literacy Action Project "National Society Science Popularization Capacity Improvement Project-Rehabilitation Science Popularization Service Capacity Improvement Action Plan"