Inherited disorders of lipid metabolism (lipoproteins, fatty acids, cholesterol and sphingolipids)

Česká verzia

Authors: Honzík Tomáš; Zeman Jiří
Authors place of work: Klinika pediatrie a dědičných poruch metabolismu, 1. lékařská fakulta, Univerzita Karlova a Všeobecná fakultní nemocnice, Praha
Published in the journal: Čes-slov Pediat 2024; 79 (5): 271-285.
Category: Chapters for Specialization in Pediatrics
doi: https://doi.org/10.55095/CSPediatrie2024/048

Summary

Introduction: Inherited disorders of lipid metabolism (IMD) represent a heterogeneous group of >210 different disorders of synthesis, transport or degradation of lipoproteins, fatty acids (FA), glycerol, ketone body, cholesterol, and complex lipids.

Material and methods: Diagnosis depends on clinical suspicion and indication of biochemical, metabolic, and molecular investigations, only six disorders of fatty acid oxidation deficiencies (FAOD) are part of the laboratory neonatal screening in the Czech Republic.

Results: Clinical manifestations of IMD of lipid metabolism are heterogeneous and may overlap in many disorders. The most common is familial autosomal dominant hypercholesterolemia (HeFH) with an incidence of 1:250. Early diagnosis and treatment in children with HeFH is essential because of the high risk for development of atherosclerosis. Disorders of lipoprotein metabolism with severe hypertriacylglycerolaemia may manifest with acute life-threatening pancreatitis, especially in lipoprotein lipase deficiency. Some IMD of lipid metabolism may manifest in embryonic period resulting in developmental defects as microcephaly, syndactyly, and hypospadia in children with Smith-Lemli-Opitz syndrome or craniofacial dysmorphia and extreme hypotonia in children with Zellweger syndrome. Children with FAOD usually manifest in neonatal period or infancy by acute attacks of hypoketotic hypoglycaemia, hepatomegaly, hepatopathy and cardiomyopathy or later by myopathy with episodic rhabdomyolysis during prolong fasting, infection or increased physical exertion. Disorders of peroxisomal oxidation of very long-chain FA manifest as leukodystrophy or neuromyelopathy and adrenal insufficiency. Disorders of lysosomal metabolism of cholesterol esters and lipids in complex molecules (sphingolipidoses) cause hepatosplenomegaly, hepatopathy and dyslipidaemia, except for Fabry disease. Main clinical problems in Gaucher disease are splenomegaly, tromobocytopenia, and bone disease, in Niemann-Pick disease types A and B interstitial lung involvement and neuropathy, and in type C vertical supranuclear gaze palsy and neuropsychiatric symptomatology. Fabry disease manifests in childhood with angiokeratomas and acroparesthesia.

Conclusion: Early diagnosis is essential for successful treatment. It involves change of lifestyle and low-fat diet in children with HeFH and LPL deficiency, frequent feeding supplemented with uncooked starches in FAOD, MCT oil supplementation in very long-chain FAOD and cholesterol supplementation in cholesterol synthesis disorders. Enzyme replacement therapy or substrate reduction therapy are used children with sphingolipidosis and impaired cholesterol ester metabolism. Hematopoietic stem cell transplantation is indicated in males at risk of the cerebral form of X-linked adrenoleukodystrophy.

Keywords:

lysosomal acid lipase deficiency – familial hypercholesterolemia – lipoprotein lipase deficiency – inherited disorders of lipid metabolism – β-oxidation of fatty acids – peroxisomal disorders – Smith-Lemli-Opitz syndrome – sphingolipidosis.

Zdroje

1. Vaz FM, Wortmann S, Mochel F. Disorders of complex lipids. In: Blau N, Dionisi Vici C, Ferreira C, et al. Physician’s guide to the diagnosis, treatment, and follow-up of inherited meetabolic diseases. 2nd ed. Cham, Switzerland: Springer 2022: 981–1025.

2. Ferreira CR, Rahman S, Keller M, et al. An international classification of inherited metabolic disorders (ICIMD). J Inherit Metab Dis 2021; 44(1): 164–177.

3. Honzík T, Kožich V, Pešková K, Votava F. Laboratorní novorozenecký screening. Ces-slov Pediat 2022; 77(1): 12–18.

4. Ramaswami U, Humphries SE. Inborn errors of lipoprotein metabolism presenting in childhood. In: Saudubray JM, Baumgartner MR, García-Cazorla A, Walter JH. Inborn Metabolic Diseases: diagnosis and treatment. 7th ed. Heidelberg: Springer 2022: 677–692.

5. Hooper AJ, Hegele RA, Burnett JR, et al. Disorders of lipoprotein metabolism. In: Blau N, Dionisi Vici C, Ferreira C, Vianey-Saban Ch, van Karnebeek CDM. Physician´s guide to the diagnosis, treatment, and follow-up of inherited meetabolic diseases. 2nd ed. Cham, Switzerland: Springer 2022: 1035–1055.

6. Florianková M, Urbanová Z, Bláhová Š, et al. Sitosterolemie: klinická, biochemická a molekulárně genetická charakteristika 3letého chlapce s významnou hypercholesterolemií. Čes-slov Pediat 2017; 72(8): 495–503.

7. Kolarova H, Tesarova M, Svecova S, et al. Lipoprotein lipase deficiency: clinical, biochemical and molecular characteristics in three patients with novel mutations in the LPL gene. Fol Biol 2014; 5(60): 235–243.

8. Honzík T, Zeman J, et al. Dědičné poruchy metabolismu v kazuistikách. Praha: Mladá fronta 2016.

9. Spiekerkoetter U, Vockley J. Mitochondrial fatty acid oxidation disorders In: Blau N, Dionisi Vici C, Ferreira C, et al. Physician’s guide to the diagnosis, treatment, and follow-up of inherited meetabolic diseases. 2nd ed. Cham, Switzerland: Springer 2022: 929–957.

10. Morris AAM, Spiekerkoetter U. Disorders of mitochondrial fatty acid oxidation and riboflavin metabolism. In: Saudubray JM, Baumgartner MR, García-Cazorla A, Walter JH. Inborn Metabolic Diseases: diagnosis and treatment. 7th ed. Heidelberg: Springer 2022: 287–301.

11. Rücklová K, Hrubá E, Pavlíková M, et al. Impact of newborn screening and early dietary management on clinical outcome of patients with long chain 3-hydroxyacyl-CoA dehydrogenase deficiency and medium chain acyl-CoA dehydrogenase deficiency – a retrospective nationwide study. Nutrients 2021; 13, 2925.

12. Honzík T, Zeman J. Výživa u dědičných metabolických poruch. In Kohout P, et al. Klinická výživa. Praha: Galén 2021: 779–798.

13. Vockley J, Burton BK, Berry G, et al. Triheptanoin for the treatment of long-chain fatty acid oxidation disorders: final results of an open-lebel, long-term extension study. J Inherit Metab Dis 2023; 46: 943–955.

14. Wanders RJA, Klouwer FCC, Engelen M, et al. Peroxisomal disorders. In: Blau N, Dionisi Vici C, Ferreira C, et al. Physician’s guide to the diagnosis, treatment, and follow-up of inherited meetabolic diseases. 2nd ed. Cham, Switzerland: Springer 2022: 1297–1317.

15. Wanders RJA, Engelen M, Vaz FM. Inborn errors of non-mitochondrial fatty acid metabolism including peroxisomal disorders. In: Saudubray JM, Baumgartner MR, García-Cazorla A, Walter JH. Inborn Metabolic Diseases: diagnosis and treatment. 7th ed. Heidelberg: Springer 2022: 785–
803.

16. Zemanová M, Chrastina P, Dvorakova L, et al. X-linked adrenoleukodystrophy: phenotype-genotype correlation in hemizygous males and heterozygous females with ABCD1 mutations. Neuro Endocrinol Lett 2021; 42(5): 359–367.

17. Formánková R, Říha P, Keslová P, et al. Transplantace kmenových buněk krvetvorby u dětí s dědičnými metabolickými poruchami a maligní infantilní osteopetrózou. Čes-slov Pediat 2022; 77(5): 276–283.

18. Mazurová S, Poupětová H, Hůlková H, et al. Nemoc ze střádání esterů cholesterolu (CESD): klinická, laboratorní a histologická charakteristika šesti pacientů. Čes-slov Pediat 2014; 69(3): 148–160.

19. Malinová V, Honzík T. Lyzozomální onemocnění – současné možnosti diagnostiky a terapie. Pediatr praxi 2013; 14(2): 99–104.

20. Honzík T, Kelifová S, Hůlková H. Dědičné poruchy metabolismu s postižením jater. In Urbánek P, Brůha R. Hepatologie 4. vydání 2022, Grada Publishing, a.s. 2022.

21. Vanier MT. Niemann-Pick disease type C. Orphanet J Rare Dis 2010; 5:16.

22. Vanier MT, Caillaud C, Levade T. Niemann-Pick disease typ C. In: Saudubray JM, Baumgartner MR, García-Cazorla A, Walter JH. Inborn Metabolic Diseases: diagnosis and treatment. 7th ed. Heidelberg: Springer 2022: 755–757.

23. Jáhnová H, Dvořáková L, Vlášková H., et al. Observational, retrospective study of a large cohort of patients with Niemann-Pick disease type C in the Czech Repbulic: a suprisingly stable diagnostic rate spannig almost 40 years. Orphanete J Rare Dis 2014; 9: 140.

24. Vanier MT, Caillaud C, Levade T. Disorders of lysosomal sphingolipid degradation: sphingolipidoses. In: Saudubray JM, Baumgartner MR, García-Cazorla A, Walter JH. Inborn Metabolic Diseases: diagnosis and treatment. 7th ed. Heidelberg: Springer 2022: 742–753.

25. Kulhánek J, Malinová V, Honzik T, Magner M. Enzymová substituční terapie u lyzozomálních nemocí. Čes-slov Pediat 2015; 70(4): 224–231.

26. Munzar P, Mazurová S, Dubská Z. Fabryho choroba v dětském věku – přehled a kazuistika. Ces-slov Pediat 2022; 77(4): 219–225.