Introduction: 2M3HBA deficiency is an X-linked disorder caused by pathogenic variants in the HSD17B10 gene (previously known as HADH2), which encodes the enzyme 17β-hydroxysteroid dehydrogenase type 10. This enzyme has a significant role in 2 major pathways: (1) the catabolism of the branched-chain amino acid isoleucine, resulting in elevated levels of acylcarnitine species when deficient, and (2) a critical component of mitochondrial RNase‐P, an enzyme complex involved in mitochondrial RNA processing whose deficiency leads to mitochondrial failure. Therefore, although it can cause transient metabolic derangements in the neonatal period and is included in the differential diagnosis for organic acidemias, the pathogenesis of disease in affected individuals is more closely related to mitochondrial dysfunction than the accumulation of toxic metabolites 1,2.
Keywords: HSD10 deficiency, HSD10 mitochondrial disease (HSD10MD), hydroxyl-CoA dehydrogenase deficiency, MHBD deficiency, organic acidemia, positive newborn screen, 17 beta-hydroxysteroid dehydrogenase type 10 (17β-HSD10) deficiency, 3-hydroxy-2-methylbutyryl-CoA dehydrogenase (3H2MBD) deficiency, 2-methyl-3-hydroxybutyric acidemia, 2-methyl-3-hydroxybutyryl-CoA dehydrogenase deficiency
Disorder Category
Organic acidemia
Mitochondrial disorder
Screening
Abnormal Finding
Elevated C5-OH
Tested By
Tandem mass spectrometry (MS/MS); sensitivity = NA; specificity = NA
Clinical Characteristics
2M3HBA deficiency has a wide range of clinical presentations, with those presenting at a younger age typically having more severe disease.
The majority will have a neurodegenerative presentation starting in infancy/early childhood with developmental delay with/without regression, choreoathetoid movements, dystonia, seizures, metabolic acidosis, cardiomyopathy, optic atrophy, and early death. Few have been reported to have normal neurological outcomes but presenting with severe ketoacidotic crises similar to beta-ketothiolase deficiency.
Females are typically asymptomatic or have a mild form of the disease due to the X-linked nature of the condition. Some females have been reported to have non-progressive developmental delays and intellectual disability.
There is currently no known treatment for 2M3HBA deficiency. Dietary modification has been attempted in some patients, but it has not been proven to change the progressive nature of the disease.
Incidence
2M3HBA deficiency is very rare, occurring in less than 1 in 1 million people3.
Inheritance
X-linked
Primary Care Management
Next Steps After a Positive Screen
- Contact the family and inform them of the result.
- Evaluate the infant for poor feeding, vomiting, or lethargy.
- Provide emergency treatment/referral for hypoglycemia, ketonuria, metabolic acidosis, or seizures.
- Consult a pediatric metabolic specialist the same day.
- Obtain confirmatory testing as recommended by the specialist.
- Provide the family with basic information about possible diagnoses and the management, including the urgent need for treatment of metabolic acidosis.
- Report final diagnostic outcome to the newborn screening program.
Confirming the Diagnosis
- To confirm the diagnosis of 2M3HBA deficiency, work with Newborn Screening Services.
- Follow-up testing may include quantitative plasma acylcarnitine profile, urine organic acids (in the infant and mother, in some cases), plasma amino acids, and genetic testing.
If the Diagnosis is Confirmed
- For evaluation and ongoing collaborative management, consult Medical Genetics.
- A dietician may work with the family to devise an optimal approach to dietary management.
- Refer the family to Genetic Testing and Counseling.
- Educate the family regarding signs, symptoms, and the need for urgent care when the infant becomes ill.
- For those identified after irreversible consequences, assist in management, particularly with low vision aids, hearing aids, or cochlear implants, and developmental and educational interventions.
Declaration of Conflicting Interests
The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.
Funding
The authors received no financial support for the research, authorship, and/or publication of this article.
References
1. Rauschenberger K, Schöler K, Sass JO, et al. A non-enzymatic function of 17beta-hydroxysteroid dehydrogenase type 10 is required for mitochondrial integrity and cell survival. EMBO Mol Med. 2010;2(2):51-62. doi:10.1002/emmm.200900055
2. Chatfield KC, Coughlin CR, Friederich MW, et al. Mitochondrial energy failure in HSD10 disease is due to defective mtDNA transcript processing. Mitochondrion. 2015;21:1-10. doi:10.1016/j.mito.2014.12.005
3. Zschocke J. HSD10 disease: clinical consequences of mutations in the HSD17B10 gene. J Inherit Metab Dis. 2012;35(1):81-89. doi:10.1007/s10545-011-9415-4
Article History
This article was originally published on the Medical Home Portal and updated before publication on TRiP. The Medical Home Portal, retired in July 2024, provided diagnosis and management information for pediatric conditions, guidance for immediate steps after a positive newborn screen result, and in-depth family education to improve outcomes for children with complex medical care needs. The full archive can be found at the Medical Home Portal Archive.
Topical Reviews in Pediatrics (TRIP) includes archival and updated content from the Medical Home Portal and features new, contemporary topics in pediatrics.
- 2018 revision: Nicola Longo, MD, PhD A
- 2012 revision: Kimberly Hart, MS, LCGCA
- 2007 first publication: Nicola Longo, MD, PhDA
AAuthor; CAContributing Author; SASenior Author; RReviewer
