PBDZSD defined

Peroxisomal biogenesis disorder-Zellweger spectrum disorder (PBDZSD) is a heterogeneous group of autosomal recessive disorders characterized by a defect in peroxisome formation, affecting multiple metabolic and biosynthetic processes.1

Behind every PBDZSD is peroxisomal dysfunction2

Peroxisomes are important organelles found throughout the body and involved in many catabolic and anabolic metabolic pathways.2

  • Functional peroxisomes are necessary for multiple key functions:
  1. Conversion of DHCA and THCA into cholic acid3
  2. Metabolism of very long–chain fatty acids (VLCFAs)1,4
  3. Degradation of VLCFAs2

The classification and phenotype of PBDZSD can vary1

PBDZSD has been historically described as 3 distinct diseases, but guidelines recommend classification based on the spectrum of disease.2,5-7

  • Severe (formerly Zellweger syndrome).
  • Intermediate (formerly neonatal adrenoleukodystrophy).
  • Less severe (formerly infantile Refsum disease).
Neonatal-infantile Zellweger syndrome features
Pediatric neonatal adrenoleukodystrophy features
Adolescent-adult infantile Refsum disease features

SEVERE

ZELLWEGER SPECTRUM2,5-7

LESS SEVERE

Neonatal-infantile Zellweger syndrome features

NEONATAL-INFANTILE

Zellweger syndrome


Severe hypotonia

Failure to thrive

Hepatomegaly

Hepatic dysfunction
(jaundice)

Craniofacial dysmorphism

Coagulopathy

Sensorineural hearing loss

Ocular abnormalities

Enamel abnormalities

Pediatric neonatal adrenoleukodystrophy features

PEDIATRIC

Neonatal adrenoleukodystrophy


Mild hypotonia

Failure to thrive

Hepatomegaly

Hepatic dysfunction

Craniofacial dysmorphism

Coagulopathy

Sensorineural hearing loss

Ocular abnormalities

Enamel abnormalities

Adolescent-adult infantile Refsum disease features

ADOLESCENT-ADULT

Infantile Refsum disease


Developmental delay

Peripheral neuropathy

Cerebellar ataxia

Leukodystrophy

Adrenal insufficiency

Sensorineural hearing loss

Ocular abnormalities

Enamel abnormalities

  • Depending on severity and progression, survival ranges from <1 year up to adulthood.2

Common features of PBD-ZSD are vision and hearing loss, hypotonia, neurological issues, and more.

Common features of PBDZSD are vision and hearing loss, hypotonia, neurological issues, developmental delay, feeding issues, and liver, kidney, and bone disease.1,2


Clinical presentation

In affected patients, the severity and range of signs and symptoms vary according to subgroup, based on age at presentation. Signs and symptoms also can vary by patient within severity subgroups, ie, not every patient will present the same way, even if they are grouped as all severe, all moderate, or all mild.1,2


Patients with milder signs and symptoms may have a delay in diagnosis, as these signs and symptoms may not appear abnormal to parents. In addition, many other diseases present similarly. Overall, common presenting signs include developmental delay and other neurologic abnormalities, vision impairment (due to retinal degeneration), sensorineural hearing loss, and evidence of liver disease.2,8

Identifying liver involvement

Nutritional issues, failure to thrive, and a depleted pool of primary bile acids may indicate liver involvement with PBD-ZSD.

Nutrition

  • Clinical assessment.
    • Clinical assessment uncovers nutritional issues, including steatorrhea and failure to thrive.1,9
    • Failure to thrive is defined as either a weight for age that falls below the fifth percentile on multiple occasions or a weight deceleration that crosses 2 major percentile lines on a growth chart.10
    • Depleted pool of primary bile acids in PBDZSD can lead to poor absorption of fats and fat-soluble vitamins, and poor growth.1,3
Patients with PBD-ZSD may have elevated LFTs (ALT, AST, or bilirubin).

Liver function tests

  • Elevated LFTs (ALT, AST, or bilirubin).1
    • Elevated ALT is strongly associated with a higher risk of all-cause and liver-associated mortality.11,12
    • If LFTs appear normal, verify the absence or presence of hepatotoxic atypical bile acids.2,4
Patients with PBD-ZSD may have accumulation of atypical bile acids (DHCA/THCA), which may indicate liver involvement in patients with PBD-ZSD.

Atypical bile acids

  • Accumulation of atypical bile acids (DHCA/THCA).4
    • Testing for the presence of DHCA and THCA is a sensitive and accurate way to detect early or subclinical liver involvement in patients with PBDZSD.4
    • Accumulation of DHCA and THCA is associated with liver involvement and disease progression.2-4

Once liver involvement is detected, appropriate care and treatment options should be initiated as early as possible.1,13

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Learn about no-cost tests for your PBDZSD patients

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REFERENCES:  1. Braverman, Raymond GV, Rizzo WB, NE et al. Peroxisome biogenesis disorders in the Zellweger spectrum: an overview of current diagnosis, clinical manifestations, and treatment guidelines. Mol Genet Metab. 2016;117(3):313-321.doi: 10.1016/j.ymgme.2015.12.009.  2. Klouwer FCC, Berendse K, Ferdinandusse S, Wanders RJA, Engelen M, Poll-The BT. Zellweger spectrum disorders: clinical overview and management approach. Orphanet J Rare Dis. 2015;10:151. doi: 10.1186/s13023-015-0368-9.  3. Baes M, Van Veldhoven PP. Hepatic dysfunction in peroxisomal disorders. Biochim Biophys Acta. 2016;1863(5):956-970. doi: 10.1016/j.bbamcr.2015.09.035.  4. Zeynelabidin S, Klouwer FCC, Meijers JCM, et al. Coagulopathy in Zellweger spectrum disorders: a role for vitamin K. J Inherit Metab Dis. 2018;41(2):249-255. doi: 10.1007/s10545-017-0113-8.  5. Braverman NE, D’Agostino MD, MacLean GE. Peroxisome biogenesis disorders: biological, clinical and pathophysiological perspectives. Dev Disabil Res Rev. 2013;17(3):187-196. doi: 10.1002/ddrr.1113.  6. Zellweger H, Maertens P, Superneau D, Wertelecki W. History of the cerebrohepatorenal syndrome of Zellweger and other peroxisomal disorders. South Med J. 1988;81(3):357-364. doi: 10.1097/00007611-198803000-00017.  7. Poll-The BT, Saudubray JM, Ogier HA, et al. Infantile Refsum disease: an inherited peroxisomal disorder. Comparison with Zellweger syndrome and neonatal adrenoleukodystrophy. Eur J Pediatr. 1987;146:477-483. doi: 10.1007/BF00441598.  8. Baumgartner MR, Poll-The BT, Verhoeven NM, et al. Clinical approach to inherited peroxisomal disorders: a series of 27 patients. Ann Neurol. 1998;44(5):720-730. doi: 10.1002/ana.410440505.  9. Berendse K, Klouwer FCC, Koot BGP, et al. Cholic acid therapy in Zellweger spectrum disorders. J Inherit Metab Dis. 2016;39(6):859-868. doi: 10.1007/s10545-016-9962-9.  10. Homan GJ. Failure to thrive: a practical guide. Am Fam Physician. 2016;94(4):295-299.  11. Kim WR, Flamm SL, Di Bisceglie AM, Bodenheimer HC Jr. Serum activity of alanine aminotransferase (ALT) as an indicator of health and disease. Hepatology. 2008;47(4):1363-1370. doi: 10.1002/hep.22109.  12. Kunutsor SK, Apekey TA, Seddoh D, Walley J. Liver enzymes and risk of all-cause mortality in general populations: a systematic review and meta-analysis. Int J Epidemiol. 2014;43(1):187-201. doi: 10.1093/ije/dyt192.  13. Setchell KDR, Balistreri WF, Piccoli DA, Clerici C. Oral bile acid therapy in the treatment of inborn errors in bile acid synthesis associated with liver disease. In: Paumgarlner G, Stiehl A, Gerok W, eds. Bile Acids as Therapeutic Agents: From Basic Science to Clinical Practice: Proceedings of the 58th Falk Symposium. Dordrecht, The Netherlands: Kluwer;1991:367-373.

INDICATION

CHOLBAM® (cholic acid) is a bile acid indicated for
  • Treatment of bile acid synthesis disorders due to single enzyme defects
  • Adjunctive treatment of peroxisomal disorders, including Zellweger spectrum disorders, in patients who exhibit manifestations of liver disease, steatorrhea, or complications from decreased fat-soluble vitamin absorption.

LIMITATIONS OF USE

The safety and effectiveness of CHOLBAM on extrahepatic manifestations of bile acid synthesis disorders due to single enzyme defects or peroxisomal disorders, including Zellweger spectrum disorders, have not been established.

IMPORTANT SAFETY INFORMATION

WARNINGS AND PRECAUTIONS – Exacerbation of liver impairment

  • Monitor liver function and discontinue CHOLBAM in patients who develop worsening of liver function while on treatment.
  • Concurrent elevations of serum gamma glutamyltransferase (GGT) and alanine aminotransferase (ALT) may indicate CHOLBAM overdose.
  • Discontinue treatment with CHOLBAM at any time if there are clinical or laboratory indicators of worsening liver function or cholestasis.

ADVERSE REACTIONS

  • The most common adverse reactions (≥1%) are diarrhea, reflux esophagitis, malaise, jaundice, skin lesion, nausea, abdominal pain, intestinal polyp, urinary tract infection, and peripheral neuropathy.

DRUG INTERACTIONS

  • Inhibitors of Bile Acid Transporters: Avoid concomitant use of inhibitors of the bile salt efflux pump (BSEP) such as cyclosporine. Concomitant medications that inhibit canalicular membrane bile acid transporters such as the BSEP may exacerbate accumulation of conjugated bile salts in the liver and result in clinical symptoms. If concomitant use is deemed necessary, monitoring of serum transaminases and bilirubin is recommended.
  • Bile Acid Binding Resins: Bile acid binding resins such as cholestyramine, colestipol, or colesevelam adsorb and reduce bile acid absorption and may reduce the efficacy of CHOLBAM. Take CHOLBAM at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after a bile acid binding resin.
  • Aluminum-Based Antacids: Aluminum-based antacids have been shown to adsorb bile acids in vitro and can reduce the bioavailability of CHOLBAM. Take CHOLBAM at least 1 hour before or 4 to 6 hours (or at as great an interval as possible) after an aluminum-based antacid.

PREGNANCY

No studies in pregnant women or animal reproduction studies have been conducted with CHOLBAM. Women who become pregnant during CHOLBAM treatment are encouraged to call 1-844-202-6262.

LACTATION

Endogenous cholic acid is present in human milk. Clinical lactation studies have not been conducted to assess the presence of CHOLBAM in human milk, the effects of CHOLBAM on the breastfed infant, or the effects of CHOLBAM on milk production. The developmental and health benefits of breastfeeding should be considered along with the mother’s clinical need for CHOLBAM and any potential adverse effects on the breastfed infant from CHOLBAM or from the underlying maternal condition.

GERIATRIC USE

It is not known if elderly patients respond differently from younger patients.

HEPATIC IMPAIRMENT

  • Discontinue treatment with CHOLBAM if liver function does not improve within 3 months of the start of treatment.
  • Discontinue treatment with CHOLBAM at any time if there are clinical or laboratory indicators of worsening liver function or cholestasis. Continue to monitor laboratory parameters of liver function and consider restarting at a lower dose when the parameters return to baseline.

OVERDOSAGE

Concurrent elevations of serum GGT and serum ALT may indicate CHOLBAM overdose. In the event of overdose, the patient should be monitored and treated symptomatically. Continue to monitor laboratory parameters of liver function and consider restarting at a lower dose when the parameters return to baseline.
To report SUSPECTED ADVERSE REACTIONS, contact Travere Therapeutics at 1‑877‑659‑5518 or FDA at 1‑800‑FDA‑1088 or www.fda.gov/medwatch.
Please see accompanying full Prescribing Information for additional Important Safety Information.