Inborn errors of

metabolism
BY :Dr Haider Nadhem
 Pattern of Inheritance

90%
10%

A.R.

2/3 X-linked 1/3 A.D

e.g. Fabry disease AIP(acute intermittent
LN syndrome porphyria),
OTC def FHC( familial hypertrophic
cardiomypoathy)
 Neonatal screening
Criteria for screening :
1disease should not appear clinically at
time of screening
2 high incidence in population screened
3 disease should treatable when
screened
4screen before irreversible change
develop
5 screen should simple and easy
It is possible to screen for a large number of
metabolic conditions during the first few days
of life, before any clinical manifestations of the
disease become apparent.
Usually treatable diseases are screened for.
PKU peripheral ulcerative keratitis .
Galactosemia .
Hypothyroidism. So that early preventable
measures could be taken .
In Iraq screening test had been launched in
2013
 Newborn Screening
NBS– What’s new?
Previously:
PKU, congenital hypothyroidism, hearing loss
Beginning April 2006:
Progressive expansion to 29 primary disorders
NBS includes hearing screening but, the focus
of this module will be on metabolic, endocrine
and hematologic conditions
20 inborn errors of metabolism

3 hemoglobinopathies

2 Congenital endocrine disorders

1 hypothyroidism
2 Congenital adrenal hyperplasia

3 other metabolic disorders

1-Cystic fibrosis
2-Galactosemia
3-Biotinidase
deficiency
The Heel Test
clinical findings suggestive
of an inborn error of
metabolism
Early
Hypoglycaemia
Metabolic acidosis
Failure to thrive
Vomiting
Fits or spasticity
Hepatosplenomegaly
Prolonged jaundice
Abnormal smell
Death of child in family and positive family history
Cataracts or retinitis pigmentosa
Late
mental retardation
Refractory rickets
Renal calculi
Neuropathy
Short stature
Dysmorphic features
 Possible laboratory investigation
of a suspected inborn error of
metabolism
Full blood count
Serum electrolytes, bicarbonate and blood gases for acid–base status
Renal function tests
Liver function tests, Plasma ammonia
Blood glucose, Urine ketones
Serum cholesterol and triglyceride,Plasma lactate , Plasma uric acid
Thyroid function tests
Porphyrins
Plasma and sometimes urine amino acids, Urine orotic acid
Urine organic acids , Plasma carnitine
Metabolites in urine or plasma by tandem mass spectroscopy
Specific enzyme assays
DNA analysis of leucocytes or fibroblasts
Many patients present with at least one of the following: metabolic
acidosis, hypoglycaemia or hyperammonaemia.
Types IBM
1. urea cycle defects
2.disorders of amino acid metabolism, ex. amino
acidurias
3. lysosomal storage defects
4. disorders of carbohydrate metabolism,ex. glycogen
storage disorders, gluconeogenesis and carbohydrate
intolerance defects
5. lipid, fatty acid oxidation defects and organic
acidurias
6. mitochondrial disorders
7. peroxisomal disorders
8. abnormalities of drug metabolism
Urea cycle disorders
Disorders of amino acid
metabolism
 Phenylketonuria
autosomal recessive disorder caused by an
abnormality of the phenylalanine
hydroxylase system.
The clinical features include:
- mental retardation
- tendency to reduced melanin formation
- irritability, feeding problems, vomiting and fits
during the first few weeks of life,
- generalized eczema.
Tyrosinaemia

presents with renal tubular dysfunction,

hypoglycaemia and severe liver disease with very
raised ALP concentration.
The defect is due to abnormal fumarylacetoacetase
leading to raised tyrosine, succinylacetone and
hydroxyphenylpyruvate.

Diagnosis is by
raised urinary succinylacetone concentration and assay
of fumarylacetoacetase in cultured leucocytes or
fibroblasts
Alkaptonuria:

is an autosomal recessive disorder

associated with a deficiency of homogentisic acid
oxidase. Homogentisic acid accumulates in tissues
and blood, and is passed in the urine. polymerization
of homogentisic acid produce
the pigment alkapton.
The deposition of alkapton in cartilages,
with consequent darkening
Albinism
A deficiency of tyrosinase in melanocytes causes one
form of albinism; it is inherited as an autosomal
recessive disorder. Pigmentation of the skin, hair and
iris is reduced and the eyes may appear pink. Reduced
pigmentation of the iris causes photosensitivity, and
decreased skin pigmentation is associated with an
increased incidence of certain skin cancers.
Homocystinuria
is an autosomal recessive disorder due to
deficiency of cystathionine synthase. These
pathways involve sulphur-containing amino
acids. Patient may show progressive central
nervous system (CNS) dysfunction, thrombotic
disease, eye disease, including cataracts, and
cardiovascular problems. The diagnosis of
homocystinuria is based on the presence of
raised urinary and plasma homocysteine with
low plasma methionine concentrations.
Maple syrup urine disease

In maple syrup urine disease, which is inherited as an

autosomal recessive condition, there is deficient
decarboxylation of the oxoacids resulting from
deamination of the three branched-chain amino
acids, leucine, isoleucine and valine. These amino
acids accumulate in the plasma and are excreted in the
urine with their corresponding oxoacids. The sweet
smell of the urine is like that of maple syrup, hence the
condition’s name
Histidinaemia
is associated with deficiency of histidinase,
an enzyme needed for normal
histidine metabolism, and is probably inherited as
an autosomal recessive trait. Some individuals
may have speech defects, but others may be
normal.
The diagnosis is made by demonstrating raised
plasma levels of histidine, and by finding
histidine and the metabolite imidazole pyruvic
acid in the urine
Amino aciduria
Amino acids are usually filtered by the glomeruli, reach the
proximal tubules at concentrations equal to those
in plasma and are almost completely reabsorbed as they
pass through this part of the nephron.
Amino aciduria may therefore be of two types. Overflow
amino aciduria In which, because of raised plasma
concentrations, amino acids reach the proximal tubules at
concentrations higher than the reabsorptive capacity of the
cells.
Renal amino aciduria In which plasma
concentrations are low because of urinary loss due to
defective tubular reabsorption.
Cystinuria

Cystinuria is the result of an autosomal recessive

inherited abnormality of tubular reabsorption, with
excessive urinary excretion, of the dibasic amino
acids cystine, ornithine, arginine and lysine

The diagnosis of cystinuria is made by demonstrating

excessive urinary excretion of the characteristic amino
acids. All these amino acids must be identified to
distinguish this from cystinuria occurring as part of a
generalized amino aciduria.
Cystinosis
This is a very rare but serious
disorder of cystine metabolism,
characterized by intracellular
accumulation and storage of
cystine in many tissues. It must be
distinguished from cystinuria, a
relatively harmles condition
Hartnup’s disease

is a rare autosomal recessive disorder in which

there are renal and intestinal transport defects
involving neutral amino acids. Many of the
clinical manifestations can be ascribed to
reduced intestinal absorption and increased
urinary loss of tryptophan
Lysosomal disorders
The mucopolysaccharidoses

Hurler’s syndrome (MPS IH) is the least

rare,and is inherited as an autosomal recessive
disorder. Patients present in infancy or early
childhood with the characteristic coarse features,
short stature, and clouding of the cornea.

Hunter’s syndrome (MPS II), in contrast to

all the other MPSs, is inherited as a sex-linked
recessive trait
The MPSs can initially
be diagnosed biochemically by
demonstrating increased urinary
excretion of sulphated
glycosaminoglycans,such as
1-dermatan
2 heparan
3 keratan sulphates
Lipid storage disorders
- GM1 gangliosidosis defect of b-galactosidase
-GM2 gangliosidosis such as Tay–Sachs disease due
to hexosaminidase deficiency

-Gaucher’s disease, due to a deficiency of

b-glucosidase (glucocerebrosidase)

- Niemann–Pick disease, resulting from

sphingomyelinase deficiency.

- Fabry’s disease, resulting from a-

galactosidase A
Carbohydrate disorders

Disorders of sugars
Galactosaemia is an autosomal
recessive disorder due to
galactose-1-phosphate uridyl
transferase (Gal-1-PUT)
deficiency
 clinical presentation
- vomiting and diarrhoea, with failure to thrive
- prolonged prothrombin time
- hepatosplenomegaly with jaundice and cirrhosis,
cataract formation
- renal tubular damage due to the deposition of
galactose-1-phosphate in the tubular cells
(Fanconi’s syndrome).
The diagnosis is made by
identifying galactose by thin-layer
chromatography and by demonstrating a
deficiency of Gal-1-PUT activity in
erythrocytes.
Urinary reducing substances are usually
positive provided the infant is on a lactose-
containing milk diet
Glycogen storage
disease
 Turkyia

Turkyia
Liver 1 3 4 6

Muscle 2 3 5 7

Riadh H ewa
1. Gas chromatography mass spectrometry
(GCMS)

• Specimen: urine
• Diagnosis of organic acidemias

Prof. Dr. H.D.El-Yassin 2017 ٤٥

 2- Tandem mass spectrometry (TMS)

• Specimen: plasma
• Diagnosis of:
– organic acidemias,
– urea cycle defects,
– Aminoacidopathies
– fatty acid oxidation
defects
Thank
yo u