Holocarboxylase/Multiple Carboxylase Deficiency
Screening
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.Incidence
Approximately 1:87,000 live births (Holocarboxylase synthetase deficiency (MedlinePlus))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:
- Metabolic acidosis
- Hyperammonemia
- Keturia
- Thrombocytopenia
- Hypoglycemia
- Elevated organic acid levels in the blood and urine
- Difficulty breathing
- Alopecia
- Motor skill delays
- Hearing loss
- Speech loss
- Spasticity
- Problems with coordination
- Seizures
- Brain damage
- Death
Follow-up Testing after Positive Screen
Quantitative plasma acylcarnitine profile, serum biotinidase assay, urine organic acids. Definitive confirmation requires enzyme assay in white blood cells or fibroblasts or DNA testing. Enzyme assay might miss mild forms due to the presence of biotin in culture media.Primary Care Management
Upon Notification of the + Screen
- Contact the family and evaluate the infant for poor feeding, vomiting, or lethargy.
- Provide emergency treatment/referral for signs/symptoms of hypoglycemia, metabolic acidosis, ketonuria, or seizures.
- To confirm the diagnosis, work with the following service(s): Newborn Screening Services (see RI providers [1]).
- For evaluation and ongoing collaborative management, consult the following service(s): Pediatric Genetics (see RI providers [4]).
If the Diagnosis is Confirmed
- Educate the family regarding signs, symptoms, and the need for urgent care when the infant becomes ill (see Holocarboxylase/Multiple Carboxylase Deficiency - Information for Parents (STAR-G) for additional information).
- Biotin supplements are indicated.
- For those identified after irreversible consequences, assist in management, particularly developmental and educational interventions.
Specialty Care Collaboration
Initial consultation with the following service(s): Pediatric Genetics (see RI providers [4]); and ongoing collaboration if the child is affected. A dietician may work with the family to devise an optimal approach to dietary management. Genetic counseling for the family.Resources
Information & Support
For Professionals
ACT Sheet for Elevated C5-OH Acylcarnitine (ACMG) (
400 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical
Genetics.
Resources for Holocarboxylase/Multiple Carboxylase Deficiency (Disease InfoSearch)
Compilation of information, articles, research, case studies, and genetics links; from Genetic Alliance.
Holocarboxylase/Multiple Carboxylase Deficiency (OMIM)
Information about clinical features, diagnosis, management, and molecular and population genetics; Online Mendelian Inheritance
in Man, authored and edited at the McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University School of Medicine
Holocarboxylase/Multiple Carboxylase Deficiency Fact Sheet (Iowa Dept. of Health)
Provides information for parents and professionals.
For Parents and Patients
Holocarboxylase/Multiple Carboxylase Deficiency - Information for Parents (STAR-G)
A fact sheet, written by a genetic counselor and reviewed by metabolic and genetic specialists, for families who have received
an initial diagnosis of this newborn disorder; Screening, Technology and Research in Genetics.
Holocarboxylase synthetase deficiency (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources;
from the National Library of Medicine.
Organic Acidemia Association (OAA)
A nonprofit organization that provides information, support, events, connections with other parents, a discussion board,
and nutrition and recipe ideas.
Tools
ACT Sheet for Elevated C5-OH Acylcarnitine (ACMG) ( 400 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive; American College of Medical
Genetics.
Services for Patients & Families in Rhode Island (RI)
| Service Categories | # of providers* in: | RI | NW | Other states (4) (show) | | MT | NM | NV | UT |
|---|---|---|---|---|---|---|---|---|---|
| Newborn Screening Services | 1 | 1 | 4 | 1 | 2 | 3 | |||
| Pediatric Genetics | 4 | 1 | 7 | 4 | 4 | 6 | |||
For services not listed above, browse our Services categories or search our database.
* number of provider listings may vary by how states categorize services, whether providers are listed by organization or individual, how services are organized in the state, and other factors; Nationwide (NW) providers are generally limited to web-based services, provider locator services, and organizations that serve children from across the nation.