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Inborn error of metabolism

Inborn errors of metabolism comprise a large class of genetic diseases involving disorders of metabolism. The majority are due to defects of single genes that code for enzymes that facilitate conversion of various substances (substrates) into others (products). In most of the disorders, problems arise due to accumulation of substances which are toxic or interfere with normal function, or to the effects of reduced ability to synthesize essential compounds. Inborn errors of metabolism are now often referred to as congenital metabolic diseases or inherited metabolic diseases, and these terms are considered synonymous. more...

ICF syndrome
Ichthyosis vulgaris
Imperforate anus
Inborn error of metabolism
Incontinentia pigmenti
Infant respiratory...
Infantile spinal muscular...
Infective endocarditis
Inflammatory breast cancer
Inguinal hernia
Interstitial cystitis
Iodine deficiency
Irritable bowel syndrome

The term inborn error of metabolism was coined by a British physician, Archibald Garrod (1857-1936), in the early 20th century. He is known for the "one gene, one enzyme" hypothesis, which arose from his studies on the nature and inheritance of alkaptonuria. His seminal text, Inborn Errors of Metabolism was published in 1923.

Major categories of inherited metabolic diseases

Traditionally the inherited metabolic diseases were categorized as disorders of carbohydrate metabolism, amino acid metabolism, organic acid metabolism, or lysosomal storage diseases. In recent decades, hundreds of new inherited disorders of metabolism have been discovered and the categories have proliferated. Following are some of the major classes of congenital metabolic diseases, with prominent examples of each class. Many others do not fall into these categories. ICD-10 codes are provided where available.

  • Disorders of carbohydrate metabolism
    • E.g., glycogen storage disease (E74.0)
  • Disorders of amino acid metabolism
    • E.g., phenylketonuria (E70.0), maple syrup urine disease (E71.0)
  • Disorders of organic acid metabolism
    • E.g., alcaptonuria (E70.2)
  • Disorders of fatty acid oxidation and mitochondrial metabolism
    • E.g., medium chain acyl dehydrogenase deficiency
  • 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
    • E.g., congenital adrenal hyperplasia (E25.0)
  • Disorders of mitochondrial function
    • E.g., Kearns-Sayre syndrome (H49.8)
  • Disorders of peroxisomal function
    • E.g., Zellweger syndrome (Q87.8)
  • Lysosomal storage disorders
    • E.g., Gaucher's disease (E75.22)

Manifestations and presentations

Because of the enormous number of these diseases and wide range of systems affected, nearly every "presenting complaint" to a doctor may have a congenital metabolic disease as a possible cause, especially in childhood. The following are examples of potential manifestations affecting each of the major organ systems:

  • Growth failure, failure to thrive, weight loss
  • Ambiguous genitalia, delayed puberty, precocious puberty
  • Developmental delay, seizures, dementia, encephalopathy, stroke
  • Deafness, blindness, pain agnosia
  • Skin rash, abnormal pigmentation, lack of pigmentation, excessive hair growth, lumps and bumps
  • Dental abnormalities
  • Immunodeficiency, thrombocytopenia, anemia, enlarged spleen, enlarged lymph nodes
  • Many forms of cancer
  • Recurrent vomiting, diarrhea, abdominal pain
  • Excessive urination, renal failure, dehydration, edema
  • Hypotension, heart failure, enlarged heart, hypertension, myocardial infarction
  • Hepatomegaly, jaundice, liver failure
  • Unusual facial features, congenital malformations
  • Excessive breathing (hyperventilation), respiratory failure
  • Abnormal behavior, depression, psychosis
  • Joint pain, muscle weakness, cramps
  • Hypothyroidism, adrenal insufficiency, hypogonadism, diabetes mellitus


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Leg Ulcers Secondary to Prolidase Deficiency
From Advances in Skin & Wound Care, 11/1/04 by Trent, Jennifer T

First described by Goodman in 1968, prolidase deficiency (PD) is a rare, autosomal recessive inborn error of collagen metabolism.1,2 It is caused by a defect in the PEPD gene on chromosome 19.3,4 As of 2004, approximately 40 cases of PD had been reported.5 In addition to its clinical features, some patients with PD develop systemic lupus erythematosus later in life, suggesting that PD may also be a risk factor for this disease.5,6

Although patients may exhibit a variety of signs and symptoms (Table 1), PD is most commonly characterized by recurrent chronic leg ulcers, typical facies, splenomegaly, and mental handicaps.1,2,5,7 Patients initially display signs of PD anytime from birth to 22 years of age, with most presenting prior to puberty.6,8,9 Ninety percent of patients manifest some dermatologie features of PD, with more than 50% suffering from chronic leg ulcers.2 Although most ulcers occur on the lower extremities, ulcerations on the upper extremities have been reported in some cases.7 Wounds related to PD are difficult to heal and frequently recur.10 They are characterized by irregular borders with prominent granulation tissue and purulent exudate. Surrounding atrophy, scarring, and lack of hair are usually present. secondaiy infection is the most common complication; however, squamous cell carcinoma develops within a long-standing leg ulcer in rare cases.10,11


Collagen is degraded to iminodipeptides, which are then broken down into amino acids that can be resynthesized to form collagen.12 One of the enzymes that degrades iminodipeptides is prolidase. Specifically, it cleaves dipeptides with proline or hydroxyproline at the C-terminus end.1,11 Decreased activity of prolidase causes a concomitant increase in urinary excretion of dipeptides (iminodipeptiduria). This iminodipeptiduria represents a deficient recycling of proline and leads to impaired collagen synthesis and wound healing.1,7,13,14

In patients with PD, amyloid deposits have been found within the vessels of the skin and internal organs, including the spleen.6 Splenic amyloid deposits lead to splenomegaly and subsequent splenic dysfunction. This may be the cause of the characteristic increased risk of infection in patients with PD.

Neutrophils have also been found to play a role in clinical manifestations of PD. Increased iminodipeptide levels lead to proliferation of neutrophils, which, in turn, generate Superoxide molecules that mediate inflammation and tissue destruction.15 In addition, neutrophils release collagenases and, along with histamine from mast cells, mediate further tissue inflammation and subsequent tissue destruction.16


PD can be diagnosed based on decreased prolidase activity in the blood and increased levels of urinary iminodipeptides.1 Prolidase is a ubiquitous enzyme; however, it exerts its greatest activity in the red blood cells and kidney.11 To determine the prolidase level, an enzyme assay of prolidase can be done using red blood cells and fibroblasts.1,11 To establish the presence of iminodipeptiduria, the patient's urine may be analyzed using urine electrophoresis on paper or thin-layer cellulose acetate and column chromatography; direct chemical ionization mass spectrometry can also detect iminodipeptiduria.2,5,11 In addition, PD can be diagnosed in utero by using chorionic villus sampling or amniocentesis.5 Laboratory abnormalities associated with PD include iron-deficiency anemia, thrombocytopenia, and hypergammaglobulinemia.6'7 However, these are neither diagnostic of nor pathognomonic for PD.

Skin histopathology is almost normal in patients with PD,2 although there may be a decrease in the size of collagen fibers or fragmentation of collagen fibers with impaired aggregation.8 Elastic fibers are normal,8 but dense bodies have been found in capillary endothelium.17 Angiopathy, perivascular neutrophilic infiltrate, dermal sclerosis, occlusion of capillary and arteriole walls with thrombi, and fibrosis of vessels walls have been demonstrated in patients with PD.17,18 Congo red staining has confirmed the presence of amyloid, which can occlude the vessels.6,15,17


Various topical, systemic, and surgical treatments for leg ulcers secondary to PD have been reported in the literature (Table 2); however, none has been shown to be effective in randomized, controlled trials. Topical antibiotics, such as gentamicin, polymyxin, and colistin, are suggested to be effective in controlling infection.12 When infection develops, oral or intravenous antibiotics become necessary.17 Topical 5% proline and 5% glycine combined in an ointment base have been shown to be more effective in healing ulcers from PD than topical 5% proline in ointment alone.13 In addition, a combination of topical and systemic growth hormone healed recalcitrant leg ulcers in 1 patient.4

Various systemic therapies that have shown efficacy in a handful of patients with leg ulcers from PD include a combination of vitamin C and manganese, with or without proline; a combination of zinc sulfate and vitamin C; and growth hormone.1-6,7,12,13,19 Periodic red blood cell transfusions and apheresis erythrocyte exchanges have also proven to be effective in healing chronic leg ulcers.6,20 Dapsone was used to heal 1 patient's recalcitrant leg ulcers.17

Surgical treatment options for ulcers secondary to PD include autologous split-thickness skin grafts or limb amputations7,17 and have been used in a few patients.


1. Berardesca E, Fideli D, Bellosta M, Dyne KM, Zanaboni G, Cetta G. Blood transfusions in the therapy of a case of prolidase deficiency. Br J Dermatol 1992;126:193-5.

2. Der Kaloustian VM, Freij BJ, Kurban AK. Prolidase deficiency: an inborn error of metabolism with major dermatological manifestations. Dermatologica 1982;164:293-304.

3. Endo F, Matsuda I. Molecular basis prolidase (peptidase D) deficiency. Mol Biol Med 1991;8:117-27.

4. Monafo V, Marseglia GL, Maghnie M, Dyne KM, Cetta G. Transient beneficial effect of GH replacement therapy and topical GH application on skin ulcers in a boy with prolidase deficiency. Pediatr Dermatol 2000;17:227-30.

5. Jaeken J. Prolidase deficiency. Orphanet Encyclopedia January 2004. Available at:; accessed September 20, 2004.

6. Bissonnette R, Friedmann D, Giroux JM, et al. Prolidase deficiency: a multisystemic hereditary disorder. J Am Acad Dermatol 1993:29:818-21.

7. Milligan A, Graham-Brown RA, Burns DA, Andersen I. Prolidase deficiency: a case report and literature review. Br J Dermatol 1989;121:405-9.

8. Leoni A, Cetta G, Tenni R, et al. Prolidase deficiency in two siblings with chronic leg ulcerations. Clinical, biochemical, and morphologic aspects. Arch Dermatol 1987;123:493-9.

9. Dyne K, Zanaboni G, Bertazzoni M, et al. Mild, late-onset prolidase deficiency: another Italian case. BrJ Dermatol 2001 ;144:635-6.

10. Fimiani M, Rubegni P, de Aloe G, Bilenchi R, Andressi L. Squamous cell carcinoma of the leg in a patient with prolidase deficiency. Br J Dermatol 1999:140:362-3.

11. Freij BJ, Der Kaloustian VM. Prolidase deficiency. A metabolic disorder presenting with dermatologie signs, Int J Dermatol 1986;25:431-3.

12. Arata J, Hatakenaka K, Oono T. Effect of topical application of glycine and proline on recalcitrant leg ulcers of prolidase deficiency. Arch Dermatol 1986;! 22:626-7.

13. Jemec GB, Moe AT. Topical treatment of skin ulcers in prolidase deficiency. Pediatr Dermatol 1996;13:58-60.

14. Arata J, Umemura S, Yamamoto Y, Hagiyama M, Nohara N. Prolidase deficiency: its dermatological manifestations and some additional biochemical studies. Arch Dermatol 1979:115:62-7.

15. Yasuda K, Ogata K, Kariya K, et al. Corticosteroid treatment of prolidase deficiency skin lesions by inhibiting iminodipeptide-primed neutrophil Superoxide generation. Br J Dermatol 1999:141:846-51.

16. KokturkA, KayaTI, Ikizoglu G, KocaA. Prolidase deficiency, Int J Dermatol 2002;41:46-8.

17. Ogata A, Tanaka S, Tomoda T, Murayama E1 Endo F, Kikuchi I. Autosomal recessive prolidase deficiency. Three patients with recalcitrant ulcers. Arch Dermatol 1981 ;117:689-97.

18. Arata J, Tada J, Yamada T, Oono T, Yasutomi H, Oka E. Angiopathic pathogenesis of clinical manifestations in prolidase deficiency. Arch Dermatol 1991;127:124-5.

19. Larreque M, Charpentier C, Laidet B, et al. Prolidase and manganese deficiency. Apropos of a case: diagnosis and treatment. Ann Dermatol Venereol 1982;109:667-78. [French]

20. Lupi A, Casado B, Soli M, et al. Therapeutic apheresis exchange in two patients with prolidase deficiency. Br J Dermatol 2002:147:1237-40.

Jennifer T. Trent, MD, and Robert S. Kirsner, MD, PhD

Jennifer T. Trent, MD, is Resident, Department of Dermatology and Cutaneous Surgery, University of Miami School of Medicine, Miami, FL. Robert S. Kirsner, MD, PhD, is Associate Professor, Department of Epidemiology and Public Health, University of Miami School of Medicine, Miami, FL, and Chief of Dermatology, Veterans Administration Medical Center, Miami, FL.

Copyright Springhouse Corporation Nov/Dec 2004
Provided by ProQuest Information and Learning Company. All rights Reserved

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