Congenital Metabolic Disorders Hs-1060

CONGENITAL METABOLIC DISORDERS HS-1060

Congenital Metabolic Disorders

OBJECTIVE

The objective of this Clinical Practice Guideline (CPG) is to provide evidence-based practice recommendations for the treatment of Congenital Metabolic Disorders and Inborn Errors of Metabolism. The CPG outlines the organizations that WellCare aligns with regarding these conditions as well as relevant Measureable Health Outcomes.

OVERVIEW

Inborn Errors of Metabolism (IEM) are the result of gene mutations related to enzymes and the co-factors for metabolism. The mutation may cause a gene to not function as well or at all. Typically the genes are inherited however mutations can occur spontaneously. Severity of symptoms is typically dependent upon two things:1

• The position of the defective enzyme within the metabolic pathway; or • The presence of any functional enzyme or co-factor being produced.

Treatment of these disorders is unique upon the disorder. Goals include minimizing or eliminating toxic metabolites that build up as the result of a block in metabolism while maintaining growth and development. Treatment options can include modified diet, supplements and/or medications.1

Congenital metabolic disorders result from the absence or abnormality of an enzyme or its cofactor, leading to either accumulation or deficiency of a specific metabolite.2 Listed below are the top IEMs with common diagnoses and epidemiology. A brief summary of symptomology is listed here; please see the Care Management section for more.

NOTE: The incidence range listed below of diagnoses is based on tw o studies – the first includes diagnoses between 1969 and 1996 in British Columbia, Canada and the second includes diagnoses betw een 1999 and 2003 in the West Midlands, United Kingdom.2

The major types of congenital metabolic disorders include:3

• Amino Acid Disorders – Phenylketonuria (PKU), Maple Syrup Urine Disease, Tyrosinemia, Homocysteinuria • Carbohydrate Disorders – Galactosemia, Glycogen Storage Disease • Lysomal Storage Diseases – categorized by involved compound or pathway: o Mucopolysaccharidoses (Hurler syndrome) o Sphingolipidoses (GM1 [monosialotetrahexosylganglioside] gangliosidosis, Tay-Sachs disease, Fabry disease, Gaucher disease, Niemann-Pick disease, Krabbe disease, metachromatic leukodystrophy, multiple sulfatase deficiency). o Glycoproteinoses (mannosidosis, sialidosis) o Disorders of lysosomal enzyme transport (mucolipidoses) o Lysosomal membrane transport disorders (sialic acid storage disease, cystinosis) o Other (lysosomal acid lipase deficiency, primary adrenal insufficiency / defects in cholesterol biochemistry) • Mitochondrial Disorders – Cytochrome c oxidase deficiency, Kearns-Sayre syndrome, Mitochondrial encephalopathy, Lactic Acidosis, MELAS (Mitochondrial Encephalopathy, Lactic acidosis, and Stroke-like episodes), MERFF (Myoclonic Epilepsy With Ragged Red Fibers), Pyruvate Dehydrogenase Deficiency • Organic Acidemias – Methylmalonic acidemia, propionic acidemia • Peroxisomal Disorders – Zellweger syndrome, Adrenoleukodystrophy • Urea Cycle Disorders – Ornithine transcarbamylase deficiency, Citrullinemia, Argininosuccinic aciduria, Argininemia

Please see the Case Management section below for a full overview of the types of Congenital Metabolic Disorders.

Other less common disorders include: • Carbohydrate Disorders (Galactosemia, Fructosemia) • Congenital Disorders of Glycosylation

Clinical Practice Guideline page 1

Original Effective Date: 1/10/2019 - Revised: N/A PRO_47086E State Approved 12172019 KY9PROWEB47086E_0000

CONGENITAL METABOLIC DISORDERS HS-1060

• Fatty Acid Oxidation Disorders (Medium chain acyl-CoA dehydrogenase deficiency, carnitine palmitoyl transferase 1 deficiency, long chain hydroxyacyl-CoA dehydrogenase deficiency) • Metal Metabolism Disorders (Wilson disease, Hemochromatosis) • Purine and Pyrimidine Disorders • Porphyrias

Hierarchy of Support GUIDELINE HIERARCHY

CPGs are updated annually or as necessary due to updates made to guidelines or recommendations by the American College of Obstetricians and Gynecologists (ACOG)]. When there are differing opinions noted by national organizations, WellCare will default to the Member’s benefit structure as deemed by state contracts and Medicaid / Medicare regulations. If there is no specific language pertaining to the Congenital Metabolic Disorders, WellCare will default (in order) to the following:

• National Committee for Quality Assurance (NCQA); • United States Preventive Services Task Force (USPSTF), National Quality Strategy (NQS), Agency for Healthcare Research and Quality (AHRQ); • Specialty associations, colleges, societies, etc. (e.g., American Academy of Family Physicians, American Congress of Obstetricians and Gynecologists, American Cancer Society, etc.).

Links to websites within the CPGs are provided for the convenience of Providers. Listings do not imply endorsement by WellCare of the information contained on these websites. NOTE: All links are current and accessible at the time of MPC approval.

WellCare aligns with ACOG on the topic of Congenital Metabolic Disorders. Highlights from their respective publications are noted below.

AMERICAN COLLEGE OF OBSTETRICIANS AND GYNECOLOGISTS (ACOG)

The American College of Obstetricians and Gynecologists (ACOG) published two practice bulletins: • Prenatal Diagnostic Testing for Genetic Disorders 4 • Screening for Fetal Aneuploidy 5

In addition, ACOG has published the following resources: • Prenatal Genetic Diagnostic Tests (FAQ 164) 6 • Prenatal Genetic Screening Tests (FAQ 165) 7

Evidence Based Practice AGENCY FOR HEALTHCARE RESEARCH AND QUALITY (AHRQ)

The Agency for Healthcare Research and Quality (AHRQ) has not published reports on this topic.

MEASUREMENT OF COMPLIANCE

WellCare is committed to adhering to the measures and standards published by the Centers for Medicare and Medicaid Services (CMS) and the National Committee for Quality Assurance (NCQA). Please reference WellCare’s Clinical Policy Guiding Document titled Quality Improvement.

NOTE: To access Clinical Policy Guiding Documents visit www.wellcare.com – select the Provider tab, then “Tools” and “Clinical Guidelines”.

Care Management

Congenital metabolic disorders result from the absence or abnormality of an enzyme or its cofactor, leading to either accumulation or deficiency of a specific metabolite. Primary symptoms for assessment and Member education for Congenital Metabolic Disorders include acute or chronic neurological and gastrointestinal manifestations, dehydration, Clinical Practice Guideline page 2

Original Effective Date: 1/10/2019 - Revised: N/A PRO_47086E State Approved 12172019 KY9PROWEB47086E_0000

CONGENITAL METABOLIC DISORDERS HS-1060

shock, lethargy, rhabdomyolysis, hypoglycemia, failure to thrive/growth delays, hepatomegaly, cardiomyopathy, and development delays. Goals include minimizing or eliminating toxic metabolites that build up as the result of a block in metabolism while maintaining growth and development. Treatment of these disorders is unique upon the disorder and can include a modified diet, supplements and/or medications.1

MEASURABLE HEALTH OUTCOMES

1. The Member reports fewer or lessening symptoms over a specific period after the start of Case Management engagement. Member-specific goals should reference Member’s individual symptoms. Compare Member’s symptom assessment responses, initial to subsequent assessments. 2. The Member experiences no symptoms requiring acute medical care and intervention. Compare pre- and post- engagement utilization frequency. Monitor for ED and inpatient authorization/utilization related to the primary diagnosis. In absence of ED and inpatient utilization, authorizations and claims data, or to otherwise demonstrate less frequent need for acute medical intervention, CM may use Provider and/or Member narrative

CASE MANAGEMENT GOALS

Case Goals should target specific care gaps and/or adherence issues, and measure the Member’s progress towards self-management and adherence, which will lead to the targeted health outcomes above. Examples: • Member’s prescription refills demonstrate at least an 80% adherence rate (verified by claims or Member/provider narrative) over last 30 days. • Member will maintain appropriate follow up with primary care provider/specialist along with appropriate laboratory testing over the last 30 days (verified by claims or Member/provider narrative) • Member describes the use of a food diary over the last 30 days and has maintained a low protein diet. • Member describes daily routine that demonstrates appropriate food choices and medication adherence. • Member describes diet and fluid intake over the last 30 days that supports adequate nutrition and hydration (per physician’s direction), to support metabolic needs. • Specific for Members requiring hospitalization: The Member participates in provider follow-up visit within 7 days of hospital discharge.

CASE MANAGEMENT OBJECTIVES

Amino Acid Disorders Includes: Phenylk etonuria (PKU)-see addendum, Maple Syrup Urine Disease, Tyrosinemia, and Homocysteinuria3

Amino Acid Disorders (or amino acidopathies) are the result of a defect in the metabolic pathways of amino acids. They are found in newborns who initially present as well but become acutely symptomatic following a time of protein feeding. Screening can be conducted using tandem mass spectrometry. Symptoms include metabolic decompensation, poor eating, lethargy). Encephalopathy, coma, or death may occur if the patient is not treated promptly. Older children typically have a developmental delay or regression.3

Amino acidemias is the result of an abnormal accumulation of amino acids in the plasma and amino acidurias when there is abnormal excretion of amino acids in the urine. Symptoms typically result from accumulation of the substance that cannot be metabolized.3

INCIDENCE: 7.6 – 18.7 per 100,000 (excludes PKU) 2 INCIDENCE: 7.5 – 8.1 per 100,000 (PKU only) 2

Case Management objectives should focus on improving the Member’s self-management skills including: • Limiting foods that exacerbate symptoms (based on specific diagnoses) • Adhering to the intake of specialized formula and/or medications per direction of the physician • Monitoring food and beverage intake each day to provide to physician for review • Providing support for Member and family through groups, therapy, and community resources

Clinical Practice Guideline page 3

Original Effective Date: 1/10/2019 - Revised: N/A PRO_47086E State Approved 12172019 KY9PROWEB47086E_0000

CONGENITAL METABOLIC DISORDERS HS-1060

Carbohydrate Disorders Includes: Galactosemia, Glycogen Storage Diseases3

Carbohydrate Disorders can lead to hypoglycemia, liver dysfunction, myopathy, and/or cardiomyopathy. Disorders include deficiencies of enzymes in the pathways of the metabolism of glycogen, galactose, and fructose. Issues include difficulty with sugar storage which can cause low blood sugar levels, muscle pain, and weakness. Other symptoms include lethargy, encephalopathy, and hypoglycemia when carbohydrate intake is low or while fasting; hepatomegaly can also be present.3

INCIDENCE: 2.3 – 6.8 per 100,000 2

Lysomal Storage Diseases Includes: Hurler Syndrome, Gaucher disease, Krabbe disease, Tay-Sachs disease3

Lysomal Storage Diseases (or “storage diseases”) result from defective lysosomal metabolism or the export of naturally occurring compounds that leads to an accumulation of various glycosaminoglycans, glycoproteins, or glycolipids within lysosomes of various tissues. The buildup of toxic substances can cause metabolic disorders. Symptoms may include progressive hepatomegaly, splenomegaly, neurologic regression, short stature, coarsening of facial features, limitation/restriction of small and large joints, peripheral neuropathy, and/or ataxia.3

INCIDENCE: 7.6 – 19.3 per 100,000 2

COMMON DIAGNOSES: Below is a summary of the Lysosomal Storage Diseases categorized by involved compound or pathway:3

• Mucopolysaccharidoses (Hurler syndrome) • Sphingolipidoses (GM1 [monosialotetrahexosylganglioside] gangliosidosis, Tay-Sachs disease, Fabry disease, Gaucher disease, Niemann-Pick disease, Krabbe disease, metachromatic leukodystrophy, multiple sulfatase deficiency). • Glycoproteinoses (mannosidosis, sialidosis) • Disorders of lysosomal enzyme transport (mucolipidoses) • Lysosomal membrane transport disorders (sialic acid storage disease, cystinosis) • Other (lysosomal acid lipase deficiency, primary adrenal insufficiency / defects in cholesterol biochemistry)

Case Management objectives should focus on improving the Member’s self-management skills including: • Providing appropriate prenatal testing and support based on diagnosis which can significantly limit the long- term effects/impact of the disease • Potential Bone Marrow Transplant options for certain diagnoses (Hurler disease) that can prevent progression of symptoms • Providing fall and aspiration precautions, as these diagnoses tend to have difficulty with swallowing, muscle tone and neurological dysfunction. • Adhering to the Enzyme Replacement Therapies/medications per direction of the physician • Providing support for Member and family through groups, therapy, and community resources

Mitochondrial Disorders

Clinical Practice Guideline page 4

Original Effective Date: 1/10/2019 - Revised: N/A PRO_47086E State Approved 12172019 KY9PROWEB47086E_0000

CONGENITAL METABOLIC DISORDERS HS-1060

Includes: Cytochrome C Oxidase Deficiency, Mitochondrial Encephalopathy, Lactic Acidosis, Kearns-Sayre syndrome, MELAS (Mitochondrial Encephalopathy, Lactic acidosis, and Strok e-lik e episodes), MERFF (Myoclonic Epilepsy With Ragged Red Fibers), Pyruvate Dehydrogenase Deficiency3

Mitochondrial Disorders present with skeletal or visceral abnormalities, poor feeding, vomiting, cardiomyopathy, myopathy, liver failure, seizures, central nervous system abnormalities, developmental delay, retinopathy, blindness, deafness, focal neurologic findings (e.g., choreoathetosis), or renal Fanconi syndrome. Biochemical features may include metabolic acidosis, lactic acidosis, hypoglycemia with appropriate or increased ketosis, and liver dysfunction3

INCIDENCE: 3.2 – 20.3 per 100,000 2

Case Management objectives should focus on improving the Member’s self-management skills including: • Providing appropriate testing and support based on diagnosis • Providing fall precaution education due to muscle weakness, muscle coordination issues, seizures, vision/hearing problems • Providing education on developmental and learning support/therapies secondary to developmental delays and learning disabilities, and autism potential. • Providing support for Member and family through groups, therapy, and community resources

Organic Acidemias Includes: Methylmalonic acidemia, propionic acidemia3

Organic Acidemias (or “organic acidurias”) are categorized by an accumulation of abnormal (and toxic) organic acid metabolites and increased excretion of organic acids in the urine. As a result, a variety of disorders can result in abnormal urine organic acid profiles (e.g., PKU, maple syrup urine disease, certain fatty acid oxidation disorders, disorders of ketogenesis, and mitochondrial disorders). Most symptoms are present during the newborn or early infancy stage. The child may be well for a period of time however it is followed by the development of a life-threatening episode of metabolic decompensation; this results in poor feeding, vomiting, and lethargy). Symptoms may progress if not treated quickly. Older children typically have a developmental delay or regression.3

INCIDENCE: 3.7 – 12.6 per 100,000 2

Peroxisomal Disorders Includes: Zellweger syndrome, Adrenoleuk odystrophy3

Peroxisomal Disorders result in an impairment of peroxisome function. The following may also be present: microcephaly, dysmorphic facial features, hepatomegaly, hypotonia, and neurologic dysfunction to a varying extent.3

INCIDENCE: 3.5 – 7.4 per 100,000 2

Clinical Practice Guideline page 5

Original Effective Date: 1/10/2019 - Revised: N/A PRO_47086E State Approved 12172019 KY9PROWEB47086E_0000

CONGENITAL METABOLIC DISORDERS HS-1060

Urea Cycle Disorders Includes: Ornithine transcarbamylase deficiency, Citrullinemia, Argininosuccinic aciduria, Argininemia

Urea Cycle Disorders is the result of a deficiency of any of the enzymes in the pathway. These disorders typically present in newborns who are initially well and become hyperammonemic after a period of protein feeding. (Those with partial enzyme activity may present later). Characteristic biochemical findings include hyperammonemia, respiratory alkalosis, and ketosis; liver dysfunction may also be present.3

INCIDENCE: 1.9 – 4.5 per 100,000 2

MEDICAL BEHAVIORAL INTEGRATION

Please note above Case Management Objectives regarding behavioral health.

MEMBER EDUCATIONAL RESOURCES

Currently there are no Krames/StayWell Member educational materials utilized by WellCare Case Managers.

Related WellCare Guidelines

In addition to the information contained in this document, please reference the following CPGs: Congenital Disorders: HS-1055; Neonatal and Infant Health: HS-1072; and Special Health Care Needs for Children: HS-1061.

NOTE: Clinical Policies can be accessed by going to www.wellcare.com – select the Provider tab, then “Tools” and “Clinical Guidelines”.

References

1. The NIH MINI Study: Metabolism, Infection and Immunity in Inborn Errors of Metabolism. National Human Genome Research Institute Web site. https://www.genome.gov/27551373/the-nih-mini-study-general-information-about-inborn-errors-of-metabolism/. Updated February 22, 2013. Accessed December 3, 2018. 2. Sutton VR. Inborn errors of metabolism: Epidemiology, pathogenesis, and clinical features. https://www.uptodate.com (subscription). Updated September 8, 2017. Accessed December 4, 2018. 3. Sutton VR. Inborn errors of metabolism: classification. https://www.uptodate.com (subscription). Updated September 2017. Accessed December 4, 2018. 4. American College of Obstetricians and Gynecologists’ Committee on Practice Bulletins—Obstetrics, Committee on Genetics, Society for Maternal–Fetal Medicine. Practice Bulletin No. 162: Prenatal Diagnostic Testing for Genetic Disorders. Obstet Gynecol. 2016 May;127(5):e108-22. Available here. 5. Committee on Practice Bulletins—Obstetrics, Committee on Genetics, and the Society for Maternal-Fetal Medicine. Practice Bulletin No. 163: Screening for Fetal Aneuploidy. Obstet Gynecol. 2016 May;127(5):e123-37. Available here. 6. Prenatal Genetic Diagnostic Tests (FAQ 164). American College of Obstetricians and Gynecologists Web site. https://www.acog.org/- /media/For-Patients/faq164.pdf?dmc=1&ts=20181107T1614127370. Updated September 2016. Accessed December 5, 2018. 7. Prenatal Genetic Screening Tests (FAQ 165). American College of Obstetricians and Gynecologists Web site. https://www.acog.org/- /media/For-Patients/faq165.pdf?dmc=1&ts=20181107T1614207839. Updated July 2017. Accessed December 5, 2018.

Disclaimer

Clinical Practice Guidelines (CPGs) made available by WellCare are informational in nature and are not a substitute for the professional medical judgment of treating physicians or other health care practitioners. CPGs are based on information available at the time and may not be updated with the most current information available at subsequent times. Individuals should consult with their physician(s) regarding the appropriateness of care or treatment options to meet their specific needs or medical condition. Disclosure of a CPG is not a guarantee of coverage and is not intended to be used for Utilization Management Decisions or for claims. Members of WellCare Health Plans should consult their individual coverage documents for information regarding covered benefits. WellCare does not offer medical advice or provide medical care, and therefore cannot guarantee any results or outcomes. WellCare does not warrant or guarantee, and shall not be liable for any deficiencies in the information contained herein or for any inaccuracies or recommendations made by independent third parties from whom any of the information contained herein was obtained. Links are current at time of approval by the Medical Policy Committee (MPC) and are subject to change. Lines of business are also subject to change without notice and are noted on www.wellcare.com. Guidelines are also available on the site by selecting the Provider tab, then “Tools” and “Clinical Guidelines”.

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Original Effective Date: 1/10/2019 - Revised: N/A PRO_47086E State Approved 12172019 KY9PROWEB47086E_0000

CONGENITAL METABOLIC DISORDERS HS-1060

WellCare (Arizona, Arkansas, Connecticut, Florida, Georgia, Illinois, Kentucky, Louisiana, Mississippi, Nebraska, New Jersey, New York, South Carolina, Tennessee, Texas)

Medical Policy Committee Approval History

Date History and Revisions by the Medical Policy Committee

1/10/2019 • Approved by MPC. New .

Clinical Practice Guideline page 7

Original Effective Date: 1/10/2019 - Revised: N/A PRO_47086E State Approved 12172019 KY9PROWEB47086E_0000