Rare Rheumatology News

Disease Profile

D-bifunctional protein deficiency

Prevalence
Prevalence estimates on Rare Medical Network websites are calculated based on data available from numerous sources, including US and European government statistics, the NIH, Orphanet, and published epidemiologic studies. Rare disease population data is recognized to be highly variable, and based on a wide variety of source data and methodologies, so the prevalence data on this site should be assumed to be estimated and cannot be considered to be absolutely correct.

Unknown

Age of onset

Infancy

ageofonset-infancy.svg

ICD-10

E71.3

Inheritance

Autosomal dominant A pathogenic variant in only one gene copy in each cell is sufficient to cause an autosomal dominant disease

no.svg

Autosomal recessive Pathogenic variants in both copies of each gene of the chromosome are needed to cause an autosomal recessive disease and observe the mutant phenotype

no.svg

X-linked
dominant X-linked dominant inheritance, sometimes referred to as X-linked dominance, is a mode of genetic inheritance by which a dominant gene is carried on the X chromosome.

no.svg

X-linked
recessive Pathogenic variants in both copies of a gene on the X chromosome cause an X-linked recessive disorder

no.svg

Mitochondrial or multigenic Mitochondrial genetic disorders can be caused by changes (mutations) in either the mitochondrial DNA or nuclear DNA that lead to dysfunction of the mitochondria and inadequate production of energy.

no.svg

Multigenic or multifactor Inheritance involving many factors, of which at least one is genetic but none is of overwhelming importance, as in the causation of a disease by multiple genetic and environmental factors.

no.svg

Not applicable

no.svg

Other names (AKA)

DBP deficiency; Peroxisomal bifunctional enzyme deficiency; PBFE deficiency;

Categories

Congenital and Genetic Diseases; Metabolic disorders

Summary

D-bifunctional protein deficiency (DBP deficiency) is a genetic disorder that affects the ability of the body to effectively break down fat from our diet. It is typically characterized by hypotonia (low muscle tone) and seizures in the newborn period. Other symptoms include unusual facial features and an enlarged liver (hepatomegaly). Most babies with this condition never gain any developmental skills and do not survive past the age of 2. DBP deficiency is caused by mutations in the HSD17B4 gene and is inherited in an autosomal recessive manner.[1]

Some researchers have suggested classifying DBP deficiency into three subtypes, depending on how severely the mutation in the HSD17B4 gene affects the function of the gene and the protein that it codes for. Almost all individuals with types I, II, and III have similar signs and symptoms. A fourth subtype has additionally been proposed for individuals that have less severe symptoms.[2]

While there is no cure for DBP deficiency, treatment is focused on improving nutrition and growth, controlling symptoms, and limiting the progression of liver disease.[3]

Symptoms

The signs and symptoms of DBP deficiency are typically very severe, with almost all children presenting with hypotonia (low muscle tone) and seizures in the first month of life. Other issues that might be present in children with DPB deficiency include:[4][1]

  • Eye problems (nystagmus, strabismus, failure to focus on objects, optic nerve atrophy, cataracts, and/or progressive vision loss)
  • Progressive hearing loss
  • Failure to achieve or loss of developmental milestones 
  • Distinct facial features (high forehead, high arched roof of the mouth (palate), enlarged soft spot (fontanelle), long philtrum, epicanthal folds, widely spaced eyes (hypertelorism), macrocephaly, retrognathia, and low-set ears)
  • Enlarged liver (hepatomegaly) 
  • Brain abnormalities (polymicrogyria, damage to the protective covering of the brain (demyelination))

This table lists symptoms that people with this disease may have. For most diseases, symptoms will vary from person to person. People with the same disease may not have all the symptoms listed. This information comes from a database called the Human Phenotype Ontology (HPO) . The HPO collects information on symptoms that have been described in medical resources. The HPO is updated regularly. Use the HPO ID to access more in-depth information about a symptom.

Medical Terms Other Names
Learn More:
HPO ID
1%-4% of people have these symptoms
Cerebral hypoplasia
Small cerebrum
Underdeveloped cerebrum

[ more ]

0006872
Decreased nerve conduction velocity
0000762
Percent of people who have these symptoms is not available through HPO
Abnormal facial shape
Unusual facial appearance
0001999
Aplasia/Hypoplasia of the cerebellum
Absent/small cerebellum
Absent/underdeveloped cerebellum

[ more ]

0007360
Autosomal recessive inheritance
0000007
Bile duct proliferation
0001408
Calcific stippling
0002832
Cerebral dysmyelination
0007266
Cholestasis
Slowed or blocked flow of bile from liver
0001396
Corpus callosum atrophy
0007371
Cortical dysplasia
0002539
Decreased muscle mass
0003199
Delayed cranial suture closure
0000270
Delayed skeletal maturation
Delayed bone maturation
Delayed skeletal development

[ more ]

0002750
Depressed nasal bridge
Depressed bridge of nose
Flat bridge of nose
Flat nasal bridge
Flat, nasal bridge
Flattened nasal bridge
Low nasal bridge
Low nasal root

[ more ]

0005280
Dolichocephaly
Long, narrow head
Tall and narrow skull

[ more ]

0000268
Elevated hepatic transaminase
High liver enzymes
0002910
Epicanthus
Eye folds
Prominent eye folds

[ more ]

0000286
Failure to thrive
Faltering weight
Weight faltering

[ more ]

0001508
Feeding difficulties in infancy
0008872
Fetal ascites
0001791
Frontal bossing
0002007
Generalized cerebral atrophy/hypoplasia
Generalized cerebral degeneration/underdevelopment
0007058
Gliosis
0002171
Global developmental delay
0001263
Hammertoe
Hammer toe
Hammertoes

[ more ]

0001765
Hepatic steatosis
Fatty infiltration of liver
Fatty liver

[ more ]

0001397
Hepatomegaly
Enlarged liver
0002240
High forehead
0000348
High palate
Elevated palate
Increased palatal height

[ more ]

0000218
Hypertelorism
Wide-set eyes
Widely spaced eyes

[ more ]

0000316
Hypoplasia of the corpus callosum
Underdevelopment of part of brain called corpus callosum
0002079
Infantile onset
Onset in first year of life
Onset in infancy

[ more ]

0003593
Large fontanelles
Wide fontanelles
0000239
Long philtrum
0000343
Low-set ears
Low set ears
Lowset ears

[ more ]

0000369
Macrocephaly
Increased size of skull
Large head
Large head circumference

[ more ]

0000256
Micrognathia
Little lower jaw
Small jaw
Small lower jaw

[ more ]

0000347
Neonatal hypotonia
Low muscle tone, in neonatal onset
0001319
Nystagmus
Involuntary, rapid, rhythmic eye movements
0000639
Osteopenia
0000938
Pectus excavatum
Funnel chest
0000767
Polyhydramnios
High levels of amniotic fluid
0001561
Polymicrogyria
More grooves in brain
0002126
Primary adrenal insufficiency
0008207
Renal cyst
Kidney cyst
0000107
Retrognathia
Receding chin
Receding lower jaw
Weak chin
Weak jaw

[ more ]

0000278
Scaphocephaly
0030799
Seizure
0001250
Split hand
Claw hand
Claw hand deformities
Claw hands
Claw-hand deformities
Split-hand

[ more ]

0001171
Strabismus
Cross-eyed
Squint
Squint eyes

[ more ]

0000486
Talipes equinovarus
Club feet
Club foot
Clubfeet
Clubfoot

[ more ]

0001762
Thoracic hypoplasia
Small chest
Small thorax

[ more ]

0005257
Undetectable electroretinogram
0000550
Upslanted palpebral fissure
Upward slanting of the opening between the eyelids
0000582
Ventriculomegaly

Cause

DBP deficiency is caused by mutations in the HSD17B4 gene. This gene codes for a special type of protein, called D-bifunctional protein, which is an enzyme (helps biochemical reactions take place). The D-bifunctional protein is found in structures within our cells called peroxisomes, which contain several different enzymes that break down different substances. The D-bifunctional protein is involved in breaking down products of fats in our diet called fatty acids. The protein has two separate parts with different enzyme activity, called hydratase and dehydrogenase domains. These domains help carry out the second and third steps of a metabolic process called the peroxisomal fatty acid beta-oxidation pathway. This pathway breaks down fatty acid molecules so they can be transported out of the peroxisomes for reuse by the cell.[1]

Mutations in the HSD17B4 gene that cause D-bifunctional protein deficiency can affect one or both of the protein's functions. Although this does not seem to affect the severity of the symptoms of the disorder, the condition may be grouped into three types based on which enzyme(s) is/are deficient:[1][2]

  • Type 1 deficiency of both enzymes
  • Type 2 deficiency of hydratase
  • Type 3 deficiency of dehydrogenase

Impairment of one or both of the protein's functions prevents the ability of the protein from breaking down fatty acids properly, resulting in a buildup of fatty acids in the body. It is not clear how the fatty acid buildup leads to the symptoms of this disorder.[1] 

Diagnosis

DBP deficiency can be diagnosed based on lab results showing increased levels of the following: (1) very long-chain fatty acids; (2) α-methyl-branched fatty acids such as pristanic acid and its precursor phytanic acid; and (3) Bile acid intermediates dihydroxycholestanoic acid (DHCA) and trihydroxycholestanoic acid (THCA). Genetic testing may be useful to confirm the diagnosis.[4][3]

Testing Resources

  • The Genetic Testing Registry (GTR) provides information about the genetic tests for this condition. The intended audience for the GTR is health care providers and researchers. Patients and consumers with specific questions about a genetic test should contact a health care provider or a genetics professional.

    Organizations

    Support and advocacy groups can help you connect with other patients and families, and they can provide valuable services. Many develop patient-centered information and are the driving force behind research for better treatments and possible cures. They can direct you to research, resources, and services. Many organizations also have experts who serve as medical advisors or provide lists of doctors/clinics. Visit the group’s website or contact them to learn about the services they offer. Inclusion on this list is not an endorsement by GARD.

    Organizations Supporting this Disease

      Organizations Providing General Support

        Learn more

        These resources provide more information about this condition or associated symptoms. The in-depth resources contain medical and scientific language that may be hard to understand. You may want to review these resources with a medical professional.

        Where to Start

        • Genetics Home Reference (GHR) contains information on D-bifunctional protein deficiency. This website is maintained by the National Library of Medicine.

          In-Depth Information

          • The Monarch Initiative brings together data about this condition from humans and other species to help physicians and biomedical researchers. Monarch’s tools are designed to make it easier to compare the signs and symptoms (phenotypes) of different diseases and discover common features. This initiative is a collaboration between several academic institutions across the world and is funded by the National Institutes of Health. Visit the website to explore the biology of this condition.
          • Online Mendelian Inheritance in Man (OMIM) is a catalog of human genes and genetic disorders. Each entry has a summary of related medical articles. It is meant for health care professionals and researchers. OMIM is maintained by Johns Hopkins University School of Medicine. 
          • Orphanet is a European reference portal for information on rare diseases and orphan drugs. Access to this database is free of charge.
          • PubMed is a searchable database of medical literature and lists journal articles that discuss D-bifunctional protein deficiency. Click on the link to view a sample search on this topic.

            References

            1. D-bifunctional protein deficiency. Genetics Home Reference. April, 2014; https://ghr.nlm.nih.gov/condition/d-bifunctional-protein-deficiency. Accessed 12/6/2016.
            2. McKusick, VA. D-BIFUNCTIONAL PROTEIN DEFICIENCY. In: Kniffin, CL. OMIM. 6/16/2014; https://www.omim.org/entry/261515. Accessed 12/6/2016.
            3. João Nascimento, Céu Mota, MDb, Lúcia Lacerda, Sara Pacheco, Rui Chorão, Esmeralda Martins, Cristina Garrido. D-Bifunctional Protein Deficiency: A Cause of Neonatal Onset Seizures and Hypotonia. Pediatric Neurology. January 24, 2015; 52(5):539-543. https://www.ncbi.nlm.nih.gov/pubmed/25882080.
            4. Ferdinandusse S, Denis S, Mooyer PAW, Dekker C, Duran M, Sorrani-Lunsing RJ et al. Clinical and Biochemical Spectrum of D-Bifunctional Protein Deficiency. Ann Neurol. 2006; 59(1):92-104. https://www.ncbi.nlm.nih.gov/pubmed/16278854.

            Rare Rheumatology News