Human pathology

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genetic metabolic diseases

inborn errors of metabolism, inherited metabolic disorders, inherited metabolic diseases, hereditary metabolic diseases

Inborn errors of metabolism are characterized by dysregulation of the metabolic networks that underlie development and homeostasis, and constitute an important and expanding group of genetic disorders in humans.

Types (summary)

- Disorders of carbohydrate metabolism

- Disorders of amino acid metabolism

- Disorders of organic acid metabolism (organic acidurias)

  • E.g., alcaptonuria (E70.2)

- Disorders of fatty acid oxidation and mitochondrial metabolism

  • E.g., medium chain acyl dehydrogenase deficiency (glutaric acidemia type 2)

- Disorders of porphyrin metabolism

  • E.g., acute intermittent porphyria (E80.2)

- Disorders of purine or pyrimidine metabolism

  • E.g., Lesch-Nyhan syndrome (E79.1)

- Disorders of steroid metabolism

- Disorders of mitochondrial function

- Disorders of peroxisomal function

  • E.g., Zellweger syndrome (Q87.8)

- Lysosomal storage disorders

  • E.g., Gaucher’s disease (E75.22)

Types (developed)

I. Defects in metabolism of amino acids

- Phenylalanine
- Tyrosine metabolism defects

  • Tyrosinemia type I
  • Tyrosinemia type II
  • Transient tyrosinemia of the newborn
  • Hawkinsinuria
  • Albinism
  • Alcaptonuria

- Sulfur-containing amino acids metabolism defects

  • Methionine
  • Homocystinemia (Homocystinuria)
    • Homocystinemia type I
    • Homocystinemia type II
    • Homocystinemia type III
  • Hypermethioninemia
  • Cystathioninemia
  • Cysteine/Cystine
  • Cystinuria
  • Cystinosis
  • Sulfite oxidase deficiency
  • beta-mercaptolate-cysteine disulfiduria
  • taurinuria

- Tryptophane

  • Hartnup disease
  • Serotonin deficiency
  • Tryptophanemia
  • Kynureninuria
  • Kynureninase defects - Hydroxykynureninuria
  • Pyridoxine-responsive xanthurenic aciduria
  • Organic acidemias
    • Indicanuria - tryptophane malapsorption
    • Hydincuria
    • Indolylacroylglycynuria
    • Glutaric aciduria type 1

- Valine, Leucine, Isoleucine and related organic acidemias
- Glycine
- Serine
- Threonine
- Proline - Hydroxyproline
- Glutamic acid
- Urea cycle (hyperammonemia) (Arginine, Citrulline, Ornithine)

  • déficit en ornithine transcarbamylase
  • déficit en carbamyl phophate synthétase
  • ornitinémie
  • citrullinémie
  • acidurie argininosuccinique
  • cystinosis
  • homocystinuria (déficit en cystathionine beta-synthase)

- Histidine
- Beta-amino acids
- Lysine
- Acide aspartique

  • Aspartylglucosaminurie

II. inherited disorders of lipid metabolism

A. Anomalies of fatty acid beta oxidation

B. Anomalies of very long chain fatty acids (peroxysomal diseases)

- Group 1. Anbormal peroxysomes (multiple enzymatic deficiency)

  • Zellweger disease
  • neonatal adrenoleukodystrophy
  • infantile REfsum disease
  • pipecolic acidemia

- Group 2. Normal peroxysome. Isolated enzymatic deficiency

  • X-linked adrenoleucodystrophy
  • acatalasemia
  • hyperoxaluria type 1
  • 3-oxoacyl-CoA thiolase deficiency (syndrome de pseudo-Zellweger)
  • acyl-CoA oxidase deficiency
  • bi-fonctionnal enzyme deficiency
  • dihydroxy-acetone-phosphate acetyl-transférase deficiency

— c. Groupe 3. Peroxysomes présents mais structure anormale. Déficits enzymatiques multiples.

  • Chondrodysplasie ponctuée rhizomélique
  • Syndrome de Zellweger-like

C. Lipid lysosomal storage diseases (lipidoses)

- sphingolipidosis

  • ceramidosis
    • glycosylceramide lipidosis (maladie de Gaucher)
    • ceramidase (Farber disease ou Farber lipogranulomatosis)
  • glycosphingolipidosis
    • Fabry disease
    • gangliosidosis type I (GM1)
    • gangliosidosis type II (GM2)
      • type I (maladie de Tay-Sachs)
      • type II (maladie de Sandhoff)
      • Niemann-Pick type D disease
      • Niemann-Pick type E disease (MIM.257200)
  • alpha-N-acétylgalactosaminidase disease (Schindler disease)
  • metachromatic leucodystrophy (sulphatide lipidosis)
  • sulfatase mutiple deficiency
  • Krabbe disease
  • Batten disease
  • Wolman disease (lysosomal lipase acide deficiency)
  • cholestérol esters storage disease
  • fucosidosis

D. Anomalies du métabolisme et du transport des lipoprotéines

- 1. hypercholestérolémie familiale
— hétérozygote
— homozygote
- 2. Déficit familial en Apo B-100
- 3. Hyperlipidémie combinée familiale
- 4. Hyperapobetalipoprotéinémie familiale
- 5. Elévation du Lp(a)
- 6. Dysbétalipoprotéinémie familiale
- 7. Sitostérolémie (Phytostérolémie)
- 8. Hypertriglycéridémie familiale (FHTG)
- 9. Hyperchylomicronémies
— Déficit en lipoprotéine lipas (LPL)
— Déficit en apoC-II (co-facteur du LPL)
— Hyperlipoprotéinémie familiale de type 5
- 10. Déficits en HDL
— déficit familial en HDL (High Density Lipoprotein) (maladie de Tangier)
— Déficit en lécithine-cholestérol acyltransférase (LCAT)
- 11. Abetalipoprotéinémie et hypobetalipoprotéinémie
- 12. Xanthomatose cérébro-tendineuse
- 13. Autres anomalies lipidiques
— Hépatostéatose familiale
— Lipodystrophie totale congénitale

III. Defects in metabolism of carbohydrates

Intestinal defects of carbohydrate metabolism Defetcs in intermediary carbohydrate metabolism
- Defetcs without lactic acidosis or abnormal glycogen storage
— Anomalies du métabolisme du galactose
— Anomalies du métabolisme du fructose
- Anomalies du métabolisme intermédiaire des glucides avec acidose lactique
- Maladie du stockage du glycogène (Glycogénoses)
- GSD O
- GSD Ia
- GSD Ib
- GSD Ic
- GSD IIa et IIb
- GSD III
- GSD IV - Amylopectinosis
- GSD V
- GSD VI
- GSD VII
- GSD VIII
- GSD IX a,b,c
- GSD X
- GSD IX

F. Déficit en Xylulose déshydrogénase G. Déficit en alpha-mannosidase acide (Mannosidose)
- déficit en alpha-fucosidase acide (Fucosidose) H. Maladie de Lafora

IV. Anomalies du métabolisme des mucopolysaccharides (Mucopolysaccharidosis ou glycprotéinoses)

A. Maladie de Hurler (Mucopolysaccharidosis IH) B. Maladie de Scheie (Mucopolysaccharidosis IS) C. Maladie de Hurler-Scheie (Mucopolysaccharidosis IH-IS) D. Maladie de Hunter (Mucopolysaccharidosis II)
- type A
- type B E. Maladie de Sanfilippo (Mucopolysaccharidosis III) (types A, B, C, D) F. Maladie de Morquio (Mucopolysaccharidosis IV) (types A, B) G. Kératane et Héparane sulfaturie (Mucopolysaccharidosis VIII) H. Maladie de Maroteaux-Lamy (Mucopolysaccharidosis VI) (mild and severe type) I. Beta-glucuronidase deficiency (Mucopolysaccharidosis VI, Sly’s syndrome) V. Anomalies du métabolisme des mucolipides (Mucolipidosis)
- Mucoplipidosis type I (ML-1) ou lipomucopolysaccharidose ou sialidose de type 2 infantile
- Mucoplipidosis type II (ML-2) (Leroy I-cell syndrome)
- Mucoplipidosis type III (ML-3) (Pseudo-Hurler polydystrophy syndrome)
- Mucoplipidosis type IV (ML-4)

VI. Anomalies of purines and pyrimidines metabolism

- Gout
- Lesh-Nyhan disease
- Hypouricémie
- Xanthinurie
- Déficit en adénosine déaminase
- Déficit en nucléoside phosphorylase
- Déficit en adénine phosphoribosyltransférase
- Acidurie orotique

VII. Anomalies du métabolisme des porphyrines (heme metabolism) (Porphyrias) Hepatic porphyrias
- porphyrie aigue intermittente
- porphyrie cutanée tardive Erythropoietic porphyrias
- protoporphyrie érythropoiétique

VIII. Anomalies du métabolisme des métaux
- cuivre
— Maladie de Wilson
- fer
— Hémochromatose constitutionnelle

IX. Anomalies of oxidative phosphorylation (OXPHOS)
- Defects in structural OXPHOS genes
- Faulty intergenomic communication
- OXPHOS assembly, homeostasis and import defects
- Mitochondrial cytopathy

IX. Anomalies vitaminiques

X. Anomalies des folates

- déficit en 5,10-@Methylenetetrahydrofolate reductase (MTHFR) (omim)

References

- Abramovich CM, Prayson RA, McMahon JT, Cohen BH.Ultrastructural examination of the axillary skin biopsy in the diagnosis of metabolic diseases.Hum Pathol. 2001 Jun;32(6):649-55. PMID: 11431721

Reviews

- Lanpher B, Brunetti-Pierri N, Lee B. Inborn errors of metabolism: the flux from Mendelian to complex diseases. Nat Rev Genet. 2006 Jun;7(6):449-60. PMID: 16708072

- Barness LA. An approach to the diagnosis of metabolic diseases. Fetal Pediatr Pathol. 2004 Jan;23(1):3-10. PMID: 15371119

- Boneh A. A model for PKC involvement in the pathogenesis of inborn errors of metabolism. Trends Mol Med. 2002 Nov;8(11):524-31. PMID: 12421686

- Abramovich CM, Prayson RA, McMahon JT, Cohen BH. Ultrastructural examination of the axillary skin biopsy in the diagnosis of metabolic diseases. Hum Pathol. 2001 Jun;32(6):649-55. PMID: 11431721

- Burton BK. Inborn errors of metabolism in infancy: a guide to diagnosis. Pediatrics. 1998 Dec;102(6):E69. PMID: 9832597

P.S.


- SIMD, Society of Inherited Metabolic Disorders

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