2M3HBA Deficiency

Guidance for primary care clinicians receiving a positive newborn screen result

Other Names

HSD10 deficiency
HSD10 mitochondrial disease (HSD10MD)
Hydroxyl-CoA dehydrogenase deficiency
MHBD deficiency
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

ICD-10 Coding

E71.118, Other branched-chain organic acidurias
E88.49, Other mitochondrial metabolism disorders

Disorder Category

Organic acidemia
Mitochondrial disorder

Screening

Abnormal Finding

Elevated C5-OH

Tested By

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

Description

2M3HBA deficiency is an X-linked disorder caused by 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 enzyme complexes involved in mitochondrial protein synthesis. Therefore, although it can cause transient metabolic derangements in the neonatal period and is included in the differential for organic acidemias, the pathogenesis of disease in affected individuals is more closely related to mitochondrial dysfunction than the accumulation of toxic metabolites. [Rauschenberger: 2010]

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 either 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 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 people. [Zschocke: 2012]

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 (see NV providers [2]).
  • Follow-up testing may include quantitative plasma acylcarnitine profile, urine organic acids (in the infant and mother, in some cases), serum biotinidase enzyme assay, plasma amino acids, and genetic testing.

If the Diagnosis is Confirmed

Resources

Information & Support

After a Diagnosis or Problem is Identified
Families can face a big change when their baby tests positive for a newborn condition. Find information about A New Diagnosis - You Are Not Alone; Caring for Children with Special Health Care Needs; Assistance in Choosing Providers; Partnering with Healthcare Providers; Top Ten Things to Do After a Diagnosis.

For Professionals

2M3HBA 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

Tools

NV ACT Sheet for ß-ketothiolase (BKT) deficiency (ACMG) (PDF Document 126 KB)
Contains short-term recommendations for clinical follow-up of the newborn who has screened positive, along with resources for consultation and patient education/support; from the American College of Genetics and Genomics

Confirmatory Algorithms for Elevated C5-OH (ACMG) (PDF Document 224 KB)
Basic steps involved in determining the final diagnosis of an infant with a positive newborn screen for this condition; American College of Medical Genetics.

Services for Patients & Families in Nevada (NV)

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.

Authors & Reviewers

Initial publication: March 2007; last update/revision: May 2024
Current Authors and Reviewers:
Author: Claire K Turscak, MD, MS
Senior Author: Brian J. Shayota, MD, MPH
Authoring history
2018: revision: Nicola Longo, MD, Ph.D.A
2012: revision: Kimberly Hart, MS, LCGCR
2007: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

Page Bibliography

Rauschenberger K, Schöler K, Sass JO, Sauer S, Djuric Z, Rumig C, Wolf NI, Okun JG, Kölker S, Schwarz H, Fischer C, Grziwa B, Runz H, Nümann A, Shafqat N, Kavanagh KL, Hämmerling G, Wanders RJ, Shield JP, Wendel U, Stern D, Nawroth P, Hoffmann GF, Bartram CR, Arnold B, Bierhaus A, Oppermann U, Steinbeisser H, Zschocke J.
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. PubMed abstract / Full Text

Zschocke J.
HSD10 disease: clinical consequences of mutations in the HSD17B10 gene.
J Inherit Metab Dis. 2012;35(1):81-9. PubMed abstract