Inherited Metabolic Disorders

What are Inherited Metabolic Disorders?

Inherited Metabolic Disorders refer to medical conditions which are caused by genetic defects mostly inherited from both parents that interfere with the body's metabolism. Metabolism is the complex set of chemical reactions that our body uses to maintain life, including energy production. Special enzymes break down food or certain chemicals so our body can use them right away for fuel or store them. Also, certain chemical processes break down substances that our body no longer needs, or make those it lacks.

IMD are a complex group of disorders, due to an inborn deficiency of a particular enzyme, functions of one or more organs are affected. The onset and severity depends on the degree of deficiency of the particular enzyme and the organ of affection. Most diseases manifest in the childhood.

What are the general symptoms?

In Children, few symptoms include
  • Apnea
  • Lethargy
  • Poor Feeding
  • Tachypnoea
  • Vomiting
There are enormous numbers of diseases with 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. Few examples of potential manifestations affecting each of the major organ systems are :
  • 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

How are Inherited Metabolic Disorders diagnosed?

They need a high index of suspicion to be diagnosed by an experienced child specialist. The confirmation is made by biochemical assay of the particular enzyme to detect its deficiency.

Common screening tests used:
  • Ferric chloride test (turned colors in reaction to various abnormal metabolites in urine)
  • Ninhydrin paper chromatography (detected abnormal amino acid patterns)
  • Guthrie bacterial inhibition assay (detected a few amino acids in excessive amounts in blood) The dried blood spot can be used for multianalyte testing using Tandem Mass Spectrometry (MS/MS). This gives an indication for a disorder. The same has to be further confirmed by enzyme assays, GC/MS or DNA Testing.
  • Quantitative measurement of amino acids in plasma and urine
  • Urine organic acid analysis by Gas chromatography-mass spectrometry
  • Plasma acylcarnitines analysis by mass spectrometry
  • Urine purines and pyrimidines analysis by Gas chromatography-mass spectrometry
Specific diagnostic tests (or focused screening for a small set of disorders):
  • Tissue biopsy or necropsy: liver, muscle, brain, bone marrow
  • Skin biopsy and fibroblast cultivation for specific enzyme testing
  • Specific DNA testing

How is Bone Marrow Transplantation (BMT) curative for these conditions?

Certain cells produced in the bone marrow produce the particular enzymes deficient in a particular disease. Only those diseases can be cured by Allogeneic BMT. However, if the brain or the heart is already severly damaged, this might not be reversed even with a successful BMT.

Which are the diseases that might be cured with a Bone Marrow Transplantation (BMT)?

  • Hurlers Syndrome
  • Morteaux-Lamy Syndrome
  • Childhood onset cerebral X-linked Leukodystrophy
  • Globoid Cell Leukodystrophy
  • Metachromatic leukodystrophy
  • α-Mannosidosis
  • Osteopetrosis etc

Who is the best donor for such BMT?

As there are rarely matched unaffected siblings, alternate donors are the best options. In certain diseases, unrelated matched cord blood provides the best source for the deficient enzyme.