Holocarboxylase Synthase Deficiency, Metabolic Disorder, Organic acid condition Screening -Infant

Holocarboxylase Synthase Deficiency, Metabolic Disorder, Organic acid condition Screening -Infant

Holocarboxylase Synthase Deficiency, Metabolic Disorder, Organic acid condition Screening

Summary of Recommendation and Evidence

Population

Recommendation

Grade
(What's This?)

Screening of both Genders

The genetic screening for Holocarboxylase synthetase deficiency is recommended.

B

Holocarboxylase synthetase deficiency (MCD) is a condition in which the body is unable to break down proteins and carbohydrates. People with this condition have trouble using biotin, a vitamin that helps turn certain carbohydrates and proteins into energy for the body. Holocarboxylase synthetase deficiency is considered an organic acid condition because it can lead to a harmful buildup of organic acids and toxins in the body. 

OVERVIEW

Caused by a a defect in holocarboxylase synthetase which is responsible for attaching biotin to four biotin-dependent enzymes, propionyl CoA carboxylase, beta-methylcrotonyl CoA, carboxylase, acetyl-CoA carboxylase, and pyruvate carboxylase. The loss of function of these enzymes impairs gluconeogenesis, results in the accumulation of multiple organic acids, in the pathways of propionic acid and leucine catabolism. This leads to inadequate energy production and the accumulation of toxic compounds leading to metabolic acidosis and other problems. Other forms of multiple carboxylase deficiency may be due to defective biotin absorption or transport or to biotinidase deficiency that in the past was known as late-onset multiple carboxylase deficiency.

SCREENING

Finding

Elevated C5:1 (methylcrotonyl or tiglyl carnitine), C5-OH (3-hydoxyisovaleryl carnitine) or C3 (propionyl carnitine)

Tested By

Tandem mass spectrometry (MS/MS); sensitivity: NA; specificity: NA

PREVALENCE

Approximately 1:87,000 live births

INHERITANCE

HCSD  is inherited in an autosomal recessive manner. It affects both boys and girls equally.

PRENATAL TESTING

DNA testing possible by amniocentesis or chorionic villus sampling (CVS) if both disease causing mutations of an affected family member have been identified.

CLINICAL CHARACTERISTICS

With treatment, most children will have normal growth and development, though some have only partly or not responded to therapy. Without treatment, repeated episodes of metabolic acidosis lead to severe impairment or death. Infants may begin to show symptoms within a few hours or days of life while other infants may not have symptoms till two years of age. Children may be healthy between metabolic crisis episodes. 

Initial signs/symptoms may include:

  • Poor feeding
  • Vomiting
  • Skin rashes
  • Lethargy
  • Lab findings:
  1. Metabolic acidosis
  2. Hyperammonemia
  3. Keturia
  4. Thrombocytopenia
  5. Hypoglycemia
  6. Elevated organic acid levels in the blood and urine

 

If not treated promptly, patients may experience:

  • Difficulty breathing
  • Alopecia
  • Motor skill delays
  • Hearing loss
  • Speech loss
  • Spasticity
  • Problems with coordination
  • Seizures
  • Brain damage
  • Death

EARLY SIGNS

Signs of holocarboxylase synthetase deficiency (MCD) begin in infancy, usually in the first few days of life. These signs include:

  • Poor appetite
  • Vomiting
  • Sleeping longer and more often 
  • Tiredness
  • Irritability
  • Weak muscle tone  (known as hypotonia)
  • Peeling skin rash
  • Hair loss (called alopecia)

Many of these signs may occur when your baby eats foods that his or her body cannot break down. They can be triggered by long periods of time without eating, illnesses, and infections.

CAUSES

When we eat food, enzymes help break it down for energy. Vitamins are also important to help our bodies break down food. In holocarboxylase synthetase deficiency (MCD), the enzyme holocarboxylase synthetase is not working correctly.

This enzyme’s job is to attach a vitamin, called biotin, to other enzymes. These other enzymes need biotin in order to break down food.

MCD occurs when your baby’s body is not making enough or making non-working holocarboxylase sythetase. When holocarboxylase synthetase is not working correctly, food cannot be broken down completely. This causes harmful substances to build up in the body.

MCD is an autosomal recessive genetic condition. This means that a child must inherit two copies of the non-working gene for MCD, one from each parent, in order to have the condition. The parents of a child with an autosomal recessive condition each carry one copy of the non-working gene, but they typically do not show signs and symptoms of the condition. While having a child with MCD is rare, when both parents are carriers, they can have more than one child with the condition.

TREATMENT

Babies with holocarboxylase synthetase deficiency (MCD) need to take biotin supplements to replace the natural biotin that is not working correctly. Biotin is a type of vitamin that your body needs to digest food. These supplements can prevent your baby from experiencing many of the signs of MCD mentioned in the Early Signs section. In some cases, biotin supplements can reverse any signs that are already present.

This is usually the only treatment your baby will need, but it is important to start treatment early to avoid any life-threatening signs and symptoms. Biotin treatment will continue throughout your child’s life. Your baby’s doctor will need to write a prescription for these supplements.

EXPECTED OUTCOMES

If your baby takes biotin supplements, he or she can live a healthy life and have typical development. With biotin treatment, your child will not need restricted diets or activities.

If holocarboxylase synthetase deficiency is not treated, children can develop seizures or permanent brain damage.