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Tyrosinemia Type 1

Overview

Tyrosinemia type 1 usually presents as severe liver problems in infants or as liver and kidney problems, decreased growth, and rickets later in life. Children with tyrosinemia type 1 can also have neurologic crises and severe abdominal pain or other neurologic problems.
Tyrosinemia type 1 results from a deficiency of fumarylacetoacetate hydrolase, which is an enzyme responsible for the breakdown of the aromatic amino acid tyrosine. The metabolite succinylacetone accumulates, resulting in toxicity to the liver and renal cells. Tyrosinemia type 1 is included in newborn bloodspot screening, identifying most affected infants using succinylacetone as the primary marker. Patients can be missed when tyrosine is used as a marker since levels can be normal in the newborn period in tyrosinemia type I. Treatment prevents most of the toxicity resulting from the enzyme deficiency.

Other Names & Coding

Fumarylacetoacetase deficiency Fumarylacetoacetate hydrolase deficiency (FAH deficiency) Hepatorenal tyrosinemia Hereditary infantile tyrosinemia Hereditary tyrosinemia type 1 Tyrosinosis
ICD-10 coding

E70.21, Tyrosinemia

Prevalence

Prevalence in the US from newborn screening data is about 1:780,000 births. [Therrell: 2014] This is likely an underestimate because data were obtained before all states implemented newborn screening using succinylacetone. The prevalence is higher in Norway and Quebec. [Bliksrud: 2012] [Giguère: 2017]

Genetics

Tyrosinemia type 1 is inherited in an autosomal recessive manner. In the general US population, the carrier frequency is estimated to be at 1:400 by newborn screening data, 1:100-1:150 from the overall prevalence of the disease, and the possibility that some cases are not identified. [Sniderman: 2017] Clinical testing for the gene responsible, fumarylacetoacetate hydrolase (FAH), is available. FAH Gene Testing (Genetic Testing Registry)

Prognosis

Untreated, affected children typically develop liver failure and die in childhood. Some children can present with isolated renal disorder. Combined medical and dietary treatment has led to a greater than 90% survival rate and prevents many complications, although there is lifelong increased risk for the development of hepatocellular carcinoma and neuropsychological problems. [Sniderman: 2017] [Schiff: 2011] Early medical therapy, coupled with diet, is very effective in preventing liver and renal disease.

Practice Guidelines

There are no published guidelines for the diagnosis or treatment of tyrosinemia type 1.

Chinsky JM, Singh R, Ficicioglu C, van Karnebeek CDM, Grompe M, Mitchell G, Waisbren SE, Gucsavas-Calikoglu M, Wasserstein MP, Coakley K, Scott CR.
Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations.
Genet Med. 2017;19(12). PubMed abstract / Full Text

de Laet C, Dionisi-Vici C, Leonard JV, McKiernan P, Mitchell G, Monti L, de Baulny HO, Pintos-Morell G, Spiekerkötter U.
Recommendations for the management of tyrosinaemia type 1.
Orphanet J Rare Dis. 2013;8:8. PubMed abstract / Full Text

Roles of the Medical Home

Medical home clinicians provide ongoing primary care and collaborate with metabolic specialists to ensure prompt referral and the initiation of dietary and medical treatment following identification through newborn screening. Supporting the family in maintaining therapy and obtaining insurance coverage for medication can be critical. Routine developmental screening and close monitoring for sequelae are important.

Clinical Assessment

Overview

Most children are diagnosed by newborn screening in the US using succinylacetone as a marker. Tyrosinemia type 1 should be suspected in any infant or child with liver disease or rickets. Even in treated children, hepatocellular carcinoma should be screened for at periodic intervals via liver ultrasound and measurement of alpha-fetorpotein.
If the child has learning or attention problems, consider neuropsychological evaluation. Episodes suggestive of neurologic crises should prompt evaluation of the amount of tyrosine restriction in the diet, nitisinone (NTBC) dosing, and/or compliance. Otherwise, treated children should have a normal clinical course.

Pearls & Alerts for Assessment

Newborn screening may miss the diagnosis

Since the tyrosine levels in newborns may be normal, screening using tyrosine as the tested analyte may miss tyrosinemia type 1.

Neuropsychological abnormalities despite treatment

Monitored for neuropsychological abnormalities, which may exist even in treated children, and provide prompt treatment as necessary. [Schiff: 2011] [van: 2019]

Neurologic crises may occur in treated children

Although the exact cause is unclear, neurologic crises can occur in individuals who are not receiving adequate doses of nitisinone (NTBC). [Schlump: 2008]

Screening

For the Condition

Newborn screening detects a high level of tyrosinemia type 1 when using succinylacetone as a biomarker for tyrosinemia type 1. [Morrissey: 2011] See Tyrosinemia Type 1 for further more information about screening and response to a positive screen.

Of Family Members

Children born to a family subsequent to the birth of a child with tyrosinemia should be screened immediately with blood and urine testing for succinylacetone to allow earliest possible treatment. This biochemical testing should be in addition to a routine newborn screen. [Sniderman: 2017] If the pathogenic variants in the family are known, prenatal molecular genetic testing of an at-risk pregnancy may be considered.

For Complications

Treatment with nitisinone greatly reduces the risk of hepatocellular carcinoma. However, one must screen for it on a regular basis, monitoring alpha-fetoprotein (AFP) and abdominal ultrasound followed by MRI if ultrasound findings are suspicious. [Chinsky: 2017] The optimal timing for screening is not clear, but it has been proposed to check AFP and perform imaging every 3-6 months. [de: 2013] Screening should be continued indefinitely. [Morrissey: 2011] [Schiff: 2011]

Presentations

Affected children may present: [Sniderman: 2017]
  1. As newborns with severe liver involvement characterized by jaundice, ascites, loss of clotting factor synthesis, and GI bleeding
  2. In the first year with
    • Liver involvement
    • Renal involvement (renal tubular dysfunction)
    • Growth failure
    • Rickets
    • Distinctive odor to the body and urine (boiled cabbage/rotten mushroom)
    • Neurologic crises
  3. As older children with rickets and with only minimal liver involvement

Differential Diagnosis

Tyrosine may also be elevated in tyrosinemia types II and III (caused by different metabolic defects), transient tyrosinemia of the newborn, liver disease, and a high-protein diet (as seen with consumption of goat’s milk in infancy). Liver abnormalities similar to those in infants with tyrosinemia type 1 may also be caused by:
  • Infection (viral – CMV, hepatitis A/B, herpes, or bacterial – sepsis, salmonella, TB)
  • Idiosyncratic drug reaction, acetaminophen toxicity, herbal medicine or mushroom poisoning
  • Metabolic disorders, including congenital disorders of glycosylation, transaldolase deficiency, mitochondrial DNA depletion syndromes
  • Any type of primary liver disease
Succinylacetone is elevated only in patients with tyrosinemia type I and is used to differentiate between this and other conditions.

Comorbid & Secondary Conditions

Neurologic crises, which occur in untreated children, are variable in presentation. A neuropathy with symptoms similar to Guillain-Barre syndrome, including diaphragmatic involvement with altered consciousness, may be noted. Abdominal pain may accompany these crises, which may resemble an acute intermittent porphyria crisis. Crises may last 1 day to 1 week. Neurologic crises that occur in a treated individual is due to a prolonged interruption in nitisinone treatment. [Sniderman: 2017]
Corneal crystals may occur if an individual has very high tyrosine levels (>700 uM/L) while being treated with nitisinone. [Sniderman: 2017]
Hepatocellular carcinoma may still occur in the treated individual and should be screened for on a routine basis. [Sniderman: 2017]

History & Examination

Current & Past Medical History

Assess adherence to dietary and treatment regimens. Be alert to symptoms that suggest neurologic involvement.

Family History

There will usually be no family history.

Developmental & Educational Progress

Observe developmental and educational progress closely. [Schiff: 2011]

Social & Family Functioning

Some families may find it hard to be consistent with the phenylalanine/tyrosine-restricted diet and nitisinone dosing. This medicine may be quite expensive and can be difficult for families to afford. Recently, additional formulations of the drug have become available, and it is hoped that the price will decrease further. Some drug manufacturers have information about payment assistance programs on their websites.

Physical Exam

Treated children should have normal general and neurologic exams.

Growth Parameters

Decreased growth may occur in untreated children.

Abdomen

Untreated children may have hepatomegaly.

Neurologic Exam

Children in crisis may present with altered mental status and peripheral neuropathy, which may cause respiratory compromise.

Testing

Laboratory Testing

Newborn screening identifies most children with this condition. In children in whom this condition is suspected, and in newborn siblings of children already identified with this disorder, testing includes measurement of succinylacetone concentration in blood and urine (in addition to routine newborn screen).
Plasma amino acids (for tyrosine and phenylalanine levels) and urine organic acids (for succinylacetone), alpha-fetoprotein, liver function tests levels, PT/PTT, and abdominal ultrasounds are followed regularly or as indicated clinically.

Genetic Testing

Testing for mutations in the gene that cause tyrosinemia type 1 (fumaryl aceto-acetic acid hydrolase (FAH)) should be performed. See FAH Gene Testing (Genetic Testing Registry).

Specialty Collaborations & Other Services

Biochemical Genetics (Metabolics) (see UT providers [3])

Children with tyrosinemia type 1 should be followed concurrently with metabolic genetics.

Developmental - Behavioral Pediatrics (see UT providers [9])

There is some evidence that treated children with tyrosinemia type 1 may have neuropsychological problems. [van: 2019] If suspected, an evaluation by a developmental pediatrician may be helpful.

Developmental Assessments (see UT providers [55])

Testing may be helpful in children suspected of having learning and attention problems.

Treatment & Management

Pearls & Alerts for Treatment & Management

Nitisinone (NTBC)

The drug used to treat tyrosinemia (2-(2-nitro-4-fluoromethylbenzoyl)-1,3-cyclohexanedione) has low toxicity but is expensive. It is given at a dose of 1 mg/kg per day. Dosage should be adjusted to maintain blood nitisinone levels between 40 and 60 µmol/L, making sure that succynylacetone normalizes in plasma or urine.

Tyrosinemia diet

An individual treated with tyrosinemia follows a low-phenylalanine and low-tyrosine diet that is adjusted based on biochemical lab values. The metabolic dietitian helps guide families through the introduction of appropriate solid foods.

Medical foods

Most individuals with tyrosinemia will take a phenylalanine and tyrosine deficient metabolic formula to meet needs for total protein, vitamins, minerals, and calories throughout life. It may be helpful to reinforce the need to brush teeth after formula, especially when given before bedtime to prevent bottle rot.

How should common problems be managed differently in children with Tyrosinemia Type 1?

Growth or Weight Gain

Growth should be normal in children with tyrosinemia type 1. If there are concerns regarding growth, please alert the metabolic dietitian so they can ensure the family understands appropriate low-tyrosine/low-phenylalanine power-packing strategies.

Development (Cognitive, Motor, Language, Social-Emotional)

Monitor motor and cognitive development at regular intervals.

Over the Counter Medications

Nitisinone is only minimally metabolized and has no known interactions with other drugs; it should be safe in combination with other medications.

Prescription Medications

Nitisinone is only minimally metabolized and has no known interactions with other drugs; it should be safe in combination with other medications. However, it could potentially inhibit CYP2C9 that metabolizes drugs such as NSAID (Ibuprofen), ACE inhibitors, and others. In clinical practice, it has been safely used in combination with common pediatric medications.

Systems

Endocrine/Metabolism

Treatment can prevent the manifestations of tyrosinemia type I except for a persisting, though small, risk for hepatocellular carcinoma if treatment is not initiated immediately after birth [Santra: 2008] and, possibly, some neuropsychological problems. [Schiff: 2011] [van: 2019]
Treatment currently involves a low tyrosine/phenylalanine diet and nitisinone (NTBC). Prior to this medication, liver transplantation was the only effective treatment. Nitisinone is initiated at 1-2 mg/kg/day and modified to reach a blood nitisinone concentration of 40-60 uM/L with the normalization of succinylacetone in plasma and urine. [Sander: 2011] [Chinsky: 2017] Although generally given twice a day, once-daily dosing may be adequate. [Schlune: 2012] [Chinsky: 2017]
If a child is diagnosed after the onset of acute liver failure, nitisinone administration leads to improvement within a few days to a week. [Santra: 2008] This medication may not be readily available in developing countries due to expense. [El-Karaksy: 2011] In the US, the need for liver transplants for tyrosinemia has decreased dramatically. [El-Karaksy: 2010]

Specialty Collaborations & Other Services

Biochemical Genetics (Metabolics) (see UT providers [3])

Children should be followed concurrently with metabolic genetics.

Nutrition/Growth/Bone

Children will be started on a low tyrosine and phenylalanine diet at diagnosis. Periodic review will be necessary to adjust the diet as needed for growth and metabolism. To achieve adequate levels of essential amino acids, children on the low tyrosine/phenylalanine restricted diet require a special formula without these amino acids but containing all others.
Individuals with tyrosinemia should have plasma amino acids regularly monitored to assess compliance with the low tyrosine, low phenylalanine diet. Individuals who are struggling to comply with the diet may need increased education, more frequent follow-up with their metabolic team, and an individualized plan to increase adherence.

Specialty Collaborations & Other Services

Nutrition, Metabolic (see UT providers [14])

Individuals will require ongoing visits.

Neurology

Patients with tyrosinemia type 1 can develop neurological problems similar to porphyria at time of acute presentation. These disappear after starting therapy. Therapy and diet have been associated with behavioral problems and decreased quality of life in patients with tyrosinemia type 1. [van: 2019] [García: 2017] [van: 2016]
No Related Issues were found for this diagnosis.

Ask the Specialist

Does nitisinone need to be given twice per day?

The current recommendations suggest dividing nitisinone into 2 daily doses for the first year of life. After this time, single daily dosing can be considered.

Why is there a need to restrict phenylalanine in addition to tyrosine?

Both phenylalanine and tyrosine are aromatic amino acids. Phenylalanine is a precursor to tyrosine and can elevate tyrosine levels if not restricted. The metabolic team will work with tyrosinemia type 1 individuals to ensure appropriate plasma levels of both phenylalanine and tyrosine to promote normal growth and development while avoiding toxic levels of tyrosine.

What screenings should be performed regularly for these individuals?

In addition to regular screenings for hepatocellular carcinoma, individuals with tyrosinemia type 1 should receive regular eye examinations through ophthalmology. The reason for this is that nitisinone treated individuals can have higher levels of tyrosine (especially if not following the diet), and this can result in tyrosine crystals forming in the eyes, which leads to corneal corrosion.

Resources for Clinicians

On the Web

Tyrosinemia Type 1 (GeneReviews)
Clinical characteristics, diagnosis/testing, management, genetic counseling, and molecular pathogenesis; from the University of Washington and the National Library of Medicine.

Helpful Articles

Articles published within the last 5 years about tyrosinemia type 1 in children

Couce ML, Dalmau J, del Toro M, Pintos-Morell G, Aldámiz-Echevarría L.
Tyrosinemia type 1 in Spain: mutational analysis, treatment and long-term outcome.
Pediatr Int. 2011;53(6):985-9. PubMed abstract

Scott CR.
The genetic tyrosinemias.
Am J Med Genet C Semin Med Genet. 2006;142C(2):121-6. PubMed abstract

de Laet C, Dionisi-Vici C, Leonard JV, McKiernan P, Mitchell G, Monti L, de Baulny HO, Pintos-Morell G, Spiekerkötter U.
Recommendations for the management of tyrosinaemia type 1.
Orphanet J Rare Dis. 2013;8:8. PubMed abstract / Full Text
Developed by a European collaboration; recommendations may not apply to the United States, particularly as they relate to early diagnosis, since tyrosinemia is now routinely screened for in the US.

Clinical Tools

Care, Action, & Self-Care Plans

UT ACT Sheet for Tyrosinemia (ACMG) (PDF Document 119 KB)
Provides recommendations for clinical and laboratory follow-up of the newborn with out-of-range screening results, along with national and local resources for clinicians and families; American College of Medical Genetics.

Care Processes & Protocols

Confirmatory Algorithm for Tyrosinemia (ACMG) (PDF Document 146 KB)
An algorithm of the basic steps involved in determining the final diagnosis of an infant with a positive newborn screen; American College of Medical Genetics.

Confirmatory Algorithms Tyrosine Normal/Elevated and SUAC Elevated (ACMG) (PDF Document 156 KB)
An algorithm of the basic steps involved in determining the final diagnosis of an infant with a positive newborn screen; American College of Medical Genetics.

Patient Education & Instructions

Hereditary Tyrosinemia Type 1 Booklet (Nutricia Metabolics) (PDF Document 7.1 MB)
Thirty-page booklet for families following a positive newborn screening.

Hereditary Tyrosinemia Type 1 Video (Nutricia Metabolics)
An 8-minute, easy-to-follow education for families after a positive newborn screening for Tyrosinemia Type-1 (HT-1).

Resources for Patients & Families

Information on the Web

Tyrosinemia Type 1 - 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.

Tyrosinemia Type 1 (MedlinePlus)
Information for families that includes description, frequency, causes, inheritance, other names, and additional resources; from the National Library of Medicine.

Tyrosinemia Type 1 (GARD)
Includes information about symptoms, inheritance, diagnosis, finding a specialist, related diseases, and support organizations; Genetic and Rare Diseases Information Center of the National Center for Advancing Translational Sciences.

National & Local Support

Tyrosinemia Society
Includes advocates, caregivers, and health professionals in order to provide education and encouragement to families living with tyrosinemia. Includes a link to a Facebook support group for tyrosinemia.

The Network of Tyrosinemia Advocates (NOTA)
Provides support and advocacy for those living with tyrosinemia. Links to the Facebook support group for tyrosinemia. Hosts an annual NOTA Camp for families living with at least one child with tyrosinemia.

Studies/Registries

Tyrosinemia Type 1 (clinicaltrials.gov)
Studies looking at better understanding, diagnosing, and treating this condition; from the National Library of Medicine.

Services for Patients & Families in Utah (UT)

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: December 2013; last update/revision: June 2020
Current Authors and Reviewers:
Author: Chelsea Norman, BS, RDN, CD
Senior Author: Nicola Longo, MD, Ph.D.
Funding: Development of this Diagnosis Module was supported in part by a grant from the US Department of Health and Human Services, Health and Human Services Administration, Maternal and Child Health Bureau (U22MC16508, CFDA 93.110), awarded to the Utah Department of Health (2009-2013).
Authoring history
2013: first version: Nicola Longo, MD, Ph.D.A
AAuthor; CAContributing Author; SASenior Author; RReviewer

Bibliography

Bliksrud YT, Brodtkorb E, Backe PH, Woldseth B, Rootwelt H.
Hereditary tyrosinaemia type I in Norway: incidence and three novel small deletions in the fumarylacetoacetase gene.
Scand J Clin Lab Invest. 2012;72(5):369-73. PubMed abstract

Chinsky JM, Singh R, Ficicioglu C, van Karnebeek CDM, Grompe M, Mitchell G, Waisbren SE, Gucsavas-Calikoglu M, Wasserstein MP, Coakley K, Scott CR.
Diagnosis and treatment of tyrosinemia type I: a US and Canadian consensus group review and recommendations.
Genet Med. 2017;19(12). PubMed abstract / Full Text

Couce ML, Dalmau J, del Toro M, Pintos-Morell G, Aldámiz-Echevarría L.
Tyrosinemia type 1 in Spain: mutational analysis, treatment and long-term outcome.
Pediatr Int. 2011;53(6):985-9. PubMed abstract

de Laet C, Dionisi-Vici C, Leonard JV, McKiernan P, Mitchell G, Monti L, de Baulny HO, Pintos-Morell G, Spiekerkötter U.
Recommendations for the management of tyrosinaemia type 1.
Orphanet J Rare Dis. 2013;8:8. PubMed abstract / Full Text
Developed by a European collaboration; recommendations may not apply to the United States, particularly as they relate to early diagnosis, since tyrosinemia is now routinely screened for in the US.

El-Karaksy H, Fahmy M, El-Raziky M, El-Koofy N, El-Sayed R, Rashed MS, El-Kiki H, El-Hennawy A, Mohsen N.
Hereditary tyrosinemia type 1 from a single center in Egypt: clinical study of 22 cases.
World J Pediatr. 2011;7(3):224-31. PubMed abstract

El-Karaksy H, Rashed M, El-Sayed R, El-Raziky M, El-Koofy N, El-Hawary M, Al-Dirbashi O.
Clinical practice. NTBC therapy for tyrosinemia type 1: how much is enough?.
Eur J Pediatr. 2010;169(6):689-93. PubMed abstract

García MI, de la Parra A, Arias C, Arredondo M, Cabello JF.
Long-term cognitive functioning in individuals with tyrosinemia type 1 treated with nitisinone and protein-restricted diet.
Mol Genet Metab Rep. 2017;11:12-16. PubMed abstract / Full Text

Giguère Y, Berthier MT.
Newborn Screening for Hereditary Tyrosinemia Type I in Québec: Update.
Adv Exp Med Biol. 2017;959:139-146. PubMed abstract

Morrissey MA, Sunny S, Fahim A, Lubowski C, Caggana M.
Newborn screening for Tyr-I: two years' experience of the New York State program.
Mol Genet Metab. 2011;103(2):191-2. PubMed abstract

Sander J, Janzen N, Terhardt M, Sander S, Gökcay G, Demirkol M, Ozer I, Peter M, Das AM.
Monitoring tyrosinaemia type I: Blood spot test for nitisinone (NTBC).
Clin Chim Acta. 2011;412(1-2):134-8. PubMed abstract

Santra S, Baumann U.
Experience of nitisinone for the pharmacological treatment of hereditary tyrosinaemia type 1.
Expert Opin Pharmacother. 2008;9(7):1229-36. PubMed abstract

Santra S, Preece MA, Hulton SA, McKiernan PJ.
Renal tubular function in children with tyrosinaemia type I treated with nitisinone.
J Inherit Metab Dis. 2008;31(3):399-402. PubMed abstract

Schiff M, Broue P, Chabrol B, De Laet C, Habes D, Mention K, Sarles J, Spraul A, Valayannopoulos V, Ogier de Baulny H.
Heterogeneity of follow-up procedures in French and Belgian patients with treated hereditary tyrosinemia type 1: results of a questionnaire and proposed guidelines.
J Inherit Metab Dis. 2011. PubMed abstract

Schlump JU, Perot C, Ketteler K, Schiff M, Mayatepek E, Wendel U, Spiekerkoetter U.
Severe neurological crisis in a patient with hereditary tyrosinaemia type I after interruption of NTBC treatment.
J Inherit Metab Dis. 2008;31 Suppl 2:S223-5. PubMed abstract

Schlune A, Thimm E, Herebian D, Spiekerkoetter U.
Single dose NTBC-treatment of hereditary tyrosinemia type I.
J Inherit Metab Dis. 2012. PubMed abstract

Scott CR.
The genetic tyrosinemias.
Am J Med Genet C Semin Med Genet. 2006;142C(2):121-6. PubMed abstract

Sniderman King L, Trahms C, Scott CR.
Tyrosinemia Type I.
GeneReviews. 2017. PubMed abstract / Full Text

Therrell BL Jr, Lloyd-Puryear MA, Camp KM, Mann MY.
Inborn errors of metabolism identified via newborn screening: Ten-year incidence data and costs of nutritional interventions for research agenda planning.
Mol Genet Metab. 2014;113(1-2):14-26. PubMed abstract / Full Text

van Ginkel WG, Jahja R, Huijbregts SC, Daly A, MacDonald A, De Laet C, Cassiman D, Eyskens F, Körver-Keularts IM, Goyens PJ, McKiernan PJ, van Spronsen FJ.
Neurocognitive outcome in tyrosinemia type 1 patients compared to healthy controls.
Orphanet J Rare Dis. 2016;11(1):87. PubMed abstract / Full Text

van Vliet K, van Ginkel WG, Jahja R, Daly A, MacDonald A, De Laet C, Vara R, Rahman Y, Cassiman D, Eyskens F, Timmer C, Mumford N, Bierau J, van Hasselt PM, Gissen P, Goyens PJ, McKiernan PJ, Wilcox G, Morris AAM, Jameson EA, Huijbregts SCJ, van Spronsen FJ.
Emotional and behavioral problems, quality of life and metabolic control in NTBC-treated Tyrosinemia type 1 patients.
Orphanet J Rare Dis. 2019;14(1):285. PubMed abstract / Full Text