Metabolic Diseases of the Nervous System

Definition
Rationale for Early Diagnosis
Clinical Clues for the Diagnosis of Metabolic Disorders
Urine Screening Tests
Serum Screening Tests
Other Screening Tests
Tissue Biopsy
Radiological Screening
Classification and Index of Metabolic Diseases

Definition

"Inborn errors of metabolism" are diseases all due to single gene defects that result in deficient or abnormal enzymes or proteins and, consequently, characteristic biochemical abnormalities. The diseases have been associated to a particular gene by forward (functional cloning) or reverse (positional cloning) genetic techniques. Because of the genetic nature, these diseases may be familial, but, rarely new mutations occur and a patient without family history may be affected.

The separation between these and other genetic diseases is arbitrary. The term "inborn errors of metabolism" here stands for diseases affecting the central nervous system and other organ systems and having a characteristic biochemical abnormality.

In general inborn errors of metabolism affect only 1 in 5000 live births but they give great insight into human genetics. Although in most cases, these diseases have been associated to a particular gene, the mechanism by which the particular genes cause the phenotype remains unknown.

Rationale for Early Diagnosis

early treatment (particularly in PKU) may improve intellectual and/or functional outcome and quality of life
genetic counseling
chance for antenatal diagnosis

Clinical Clues to Metabolic Diseases

history of same syndrome in siblings or close relative
recurrent episodes of altered consciousness or vomiting in an infant
recurrent or progressive ataxia or spasticity
mental retardation in sibling or close relative
mental retardation in the absence of major congenital anomalies
dysmorphic features

More clinical clues in metabolic disorders

Clue	Diagnosis
Cutaneous Abnormalities
Increased pigmentation	Adrenoleukodystrophy
Telangiectases	Ataxia-telangiectasia
Perioral eruption	Multiple carboxylase deficiency
Absent adipose tissue	Cockayne syndrome
Angiokeratoma	Fabry, Sialidosis, fucosidosis type2
Oculocutaneous albinism	Chediak-Higashi syndrome
Xanthomas	Cerebrotendinous xanthomatosis
Subcutaneous nodules	Ceramidosis (Farber d.)
Ichthyosis	Sj` gren-Larrson syndrome
	Refsum disease
	Dorfman-Chanarin syndrome
Abnormal Urinary or Body Odor
Musty	PKU
Maple syrup or caramel	Maple syrup urine disease
Sweaty feet or ripe cheese	Isovaleric acidemia
Sweaty feet	Glutaric acidemia type 2
Cat urine	3-methylcrotonyl CoA carboxylase deficiency
Cat urine	Multiple carboxylase deficiency
Hair Abnormalities
Alopecia	Multiple carboxylase deficiency
Kinky hair	Kinky hair disease
	Arginosuccinic aciduria
	Multiple carboxylase deficiency
	Giant axonal neuropathy
	Trichothyodystrophy (Pollit syndrome)
Unusual Facies	Muchopolysaccharidosis (Hunter-Hurler)
Coarse	Sanfilippo syndrome
Slight coarsening	Mucolipidosis type 3 (pseudo-Hurler)
	Fucosidosis type 2
	Mannosidosis
	Sialodosis type 2
	Aspartylglucosaminuria

Ocular Abnormalities
Cataracts	Galactosemia
	Cerebrotendinous xanthomatosis
	Homocystinuria
	Cockayne syndrome
Corneal clouding	Hurler syndrome
	Hunter syndrome (late severe cases)
	Morquio syndrome
	Maroteaux-Lamy syndrome
Cherry-red spot	Tay-Sachs d. , Sandhoff d. (GM2 gangliosidosis)
	GM1 gangliosidosis (infantile)
	Niemann-Pick disease (type A and C)
	Infantile Gaucher disease (type II)
	Sialidosis

Commonly used Urine Screening Tests

Condition	FeCl3	DNPH	Benedict	Nitroprusside	Acid Albumin	Diazotized p-nitroaniline
PKU	Green	+	-	-	-	-
Maple syrup urine d.	Navy blue	+	-	-	-	-
Tyrosinosis	Pale green (transient)	+	+/-	-	-	-
Histidinemia	Green-brown (permanent)	+/-	-	-	-	-
Propionic acidemia	Purple	+	-	-	-	-
Methylmalonic acidemia	Purple	+	-	-	-	+
Homocystinuria	-	-	-	+	-	-
Glutathioninuria	-	-	-	+	-	-
Cystinuria	-	-	-	+	-	-
Mucopolysaccharidosis	-	-	-	-	+	-
Galactosemia	-	-	+	-	-	-
Fructose intolerance	-	-	+	-	-	-

Blood Screening Tests

Common biochemical findings in patients with IEM:

Hyperammonemia
Hypoglycemia
Intermittent acidosis
Elevated pyruvic acid and/or lactic acid, CSF or serum

Thus, the initial work up should include:

Ammonia levels
Magnesium levels
*Chemistry panel
Arterial Blood Gases
Serum and/or CSF lactic and pyruvic acid levels
** serum and urine uric acid
** serum cholesterol
*** immunoglobulin electrophoresis
Thyroid function tests
***Serum copper
***Ceruloplasmin

** more specific tests, with high suspicion for a specific disorder

* and ** all included in SMA20

***only if specific entities suspected

If the suspicion continues to be high, the tests should be repeated with the child in a high-protein or high-carbohydrate diet, depending on the initial test abnormalities.

If elevated lactic acid is found, one should order:

urinary amino acids
urinary carboxylic acids

These tests will confirm lactic acidemia and disclose the specific abnormality of amino acid or carboxylic acid abnormality.

If adrenoleukodystrophy is suspected: very long-chain fatty acids.

Additional tests:

2-dimensional paper chromatography for urinary amino acids
urinary organic acids

Serum Lysosomal Enzyme Screen

beta-galactosidase
arylsulfatase
hexosaminidases
oligosaccharides (by fluorophore-assisted carbohydrate electrophoresis)

Tissue biopsy

Though rarely indicated, tissue biopsy and/or enzyme assays are necesary for the diagnosis of certain diseases. Here is a list of the tissue biopsy types and the diseases they can help diagnose:

Brain Biopsy (all lipidoses, degenerative diseases of the gray or white matter).

Muscle biopsy (ceroid lipofucsinosis, familial myoclonus epilepsy, lactic acidoses).

Bone marrow biopsy (Niemann-Pick disease, Gaucher disease, GM1 gangliosidosis).

Peripheral Nerve Biopsy (Refsum disease, Metachromatic leukodystrophy, infantile neuroaxonal dystrophy, Fabry disease, Tangier disease).

Liver biopsy (Wilson, Kinky Hair, etc).

Skin, conjunctiva, lymphocyte biopsy/pathology (most lipidoses, Lafora body disease, Neuraxonal dystrophy, mucolipidosis, Sanfilippo syndromes, Fabry disease).

Radiology

Radiologic tests may help diagnose the mucopoplysaccharidoses, Gaucher disease, Niemann-Pick disease and GM1 gangliosidosis.

Classification and Index to Metabolic Diseases

Inborn errors of metabolism are classified according to the abnormal biochemical pathway or according to the substance that is abnormally metabolized. Hence the following groups of diseases are acknowledged:

Disorders of
Disorders of Amino Acid Transport

Disorders of Lipid Metabolism
Lysosomal and Peroxisomal Disorders
Disorders of Purine and Pyrimidine Metabolism
Disorders of Metal Metabolism
Familial Myoclonic Epilepsies