2M3HBA Deficiency
Guidance for primary care clinicians receiving a positive newborn screen result
Other Names
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
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 NW providers [1]).
- 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
- For evaluation and ongoing collaborative management, consult Medical Genetics (see NW providers [1]).
- A dietician may work with the family to devise an optimal approach to dietary management. See Nutrition, Metabolic (see NW providers [11]).
- Refer the family to Genetic Testing and Counseling (see NW providers [5]).
- 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, such as Early Intervention for Children with Disabilities/Delays (see NW providers [3]).
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
ACT Sheet for Elevated C5-OH Acylcarnitine (ACMG) (
336 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) ( 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 Nationwide (NW)
| Service Categories | # of providers* in: | NW | Partner states (4) (show) | | NM | NV | RI | UT | |
|---|---|---|---|---|---|---|---|---|---|
| Early Intervention for Children with Disabilities/Delays | 3 | 34 | 30 | 13 | 51 | ||||
| Genetic Testing and Counseling | 5 | 5 | 11 | 7 | 10 | ||||
| Medical Genetics | 1 | 2 | 5 | 4 | 7 | ||||
| Newborn Screening Services | 1 | 3 | 2 | 2 | 3 | ||||
| Nutrition, Metabolic | 11 | 11 | 13 | 13 | 11 | ||||
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.
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