Beta-ketothiolase deficiency: etiology and epidemiology, clinical manifestations, diagnosis, and treatment

Beta-ketothiolase deficiency (BKD), also known as mitochondrial acetoacetyl-CoA thiolase deficiency, is a rare autosomal recessive metabolic disease

The etiology and epidemiology

Beta-ketothiolase plays an important role in isoleucine metabolism and ketone body breakdown, it is responsible for catalyzing step 6 of isoleucine metabolism from 2-methyl-acetoacetyl-CoA to acetyl-CoA A and propionyl-CoA also catalyze acetoacetyl-CoA to acetyl-CoA during ketone body decomposition and fatty acid oxidation

The ACAT1 gene is located at 11q22.

2.

The incidence of the disease is 1/333 000~1/111 000, and there are great differences in different countries and regions

Beta-ketothiolase deficiency is a rare autosomal recessive metabolic disorder with only 50 to 60 cases reported worldwide

3.

Infancy and childhood onset

About 1/5 of the cases have changes in the nervous system, manifested as cognitive impairment, mental retardation, extrapyramidal abnormalities, and symptoms of stroke.

Patients can be asymptomatic in the early stage, and are diagnosed in the neonatal period or high-risk groups through blood and urine metabolic screening

4.

For patients with ketoacidosis in infants and young children, high vigilance should be carried out, and urine organic acid analysis, blood amino acid and acylcarnitine profile analysis, and genetic testing should be carried out as soon as possible.

1.

2.

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V.
Differential Diagnosis

1.
The clinical manifestations and routine biochemical tests of β-ketothiolase deficiency are similar to other organic acidemias with increased C5OH, and need to be compared with 3-methylcrotonyl-CoA carboxylase deficiency, 3-hydroxy-3- Differentiation of methylglutaryl-CoA lyase deficiency
.
The main point of identification is to perform blood acylcarnitine spectrum and urine organic acid analysis at the same time.
In addition to the increase of C5OH, the former is accompanied by the increase of C4OH and C5:1, and 2-methyl-3-hydroxybutyric acid can be detected in urine.
, Methylcrotonylglycine and 3-hydroxybutyric acid were significantly increased
.

2.
When accompanied by elevated blood sugar, it needs to be differentiated from diabetic ketoacidosis
.

6.
Treatment

The principles of treatment are timely correction of acidosis, a high-calorie diet, and the reduction of ketoacidosis and hypoglycemia episodes as much as possible
.

1.
Acute attack period

Intravenous infusion of glucose, electrolyte solution and levocarnitine, etc.
, ensures sufficient fluid intake, promotes the excretion of organic acid metabolites, provides sufficient calorie supply, reduces protein decomposition, and reduces the production of acidic substances
.
At the same time, bicarbonate is given according to individual circumstances, and severe patients require hemodialysis or plasma exchange
.
L-carnitine can form acylcarnitine with organic acid metabolites, which is beneficial to the excretion of organic acids
.
Relieve the inducing factors such as fever and infection, and inject glucose intravenously to reduce the continuous decomposition of protein and ensure the supply of heat.
2.
Stable treatment
.

Eat normally, eat small, frequent meals, avoid prolonged fasting, avoid fatigue, limit protein slightly to avoid excessive intake of isoleucine, and take care to avoid high-fat diets
.
Oral administration of L-carnitine helps stabilize metabolic status
.

Another study reported that insulin is indeed effective in the treatment of non-diabetic ketoacidosis in patients with BKD
.

Seven, diagnosis and treatment process

8.
Prognosis

Most children with β-ketothiolase deficiency can fully recover and develop normally if they can be diagnosed and properly treated at the first attack
.
If not diagnosed and treated in time, acidosis may occur repeatedly in children, severe cases may die, and survivors may be left with severe neurological sequelae
.
Therefore, timely and reasonable treatment and long-term management are very important to improve the prognosis
.

9.
Rare Disease Information Registration

If you are willing to seek continuously updated information, it is recommended that you register the patient's information here, even if it is not fully diagnosed, you can register, click to enter:

Rare Disease Patient Information Registry

References:

Nguyen KN, Abdelkreem E, Colombo R, et al.
Characterization and outcome of 41 patients with beta-ketothiolase deficiency: 10 years' experience of a medical center in northern Vietnam.
J Inherit Metab Dis, 2017, 40(3):395- 401.

Hong Fang, Huang Xinwen, Zhang Yu, et al.
Screening and follow-up analysis of neonatal organic aciduria in Zhejiang Province.
Journal of Zhejiang University (Medical Edition), 2017, 46(3): 240-247.

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