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Chapter: Paediatrics: Inherited metabolic disease

Paediatrics: Metabolic syndromes: neurological

There are 7 presentations of IMD with neurological features.

Metabolic syndromes: neurological


There are 7 presentations of IMD with neurological features.


Chronic encephalopathy


Grey matter: developmental delay, psychomotor retardation


Developmental delay is a common problem, but the features that warrant investigation for IMD include:

   Global delay affecting all areas of development.

   Progressive course with loss of developmental milestones.

   Objective evidence of neurological dysfunction (e.g. special senses, pyramidal tract, extrapyramidal, cranial nerves).

   Severe behaviours including irritability, impulsiveness, aggressiveness, and hyperactivity.

   Seizures (complex partial or myoclonic) originating early in life that are resistant to usual therapy.


Causes include vitamin B6 dependency; biotinidase deficiency; neuronal ceroid-lipofuscinosis; GM2 gangliosidosis; cherry-red spot–myoclonus syn-drome (sialidosis type I); Leigh disease; Alper’s disease; MELAS (mitochon-drial encephalopathy–lactic acidosis and stroke-like episodes syndrome).


White matter: gross motor delay, weakness, and incoordination


   Central involvement only: Canavan disease; Alexander disease; GM2 gangliosidosis; GM1 gangliosidosis; X-linked adrenoleucodystrophy (ALD); amino acidurias, organic acidurias.


   Central and peripheral involvement: metachromatic leucodystrophy (MLD); Krabbe leucodystrophy; peroxisomal disorders.


Chronic encephalopathy with abnormalities outside the CNS


   Muscle: mitochondrial myopathy.

   Hepatosplenomegaly +/– bone: Gaucher disease, Niemann–Pick disease, mucopolysaccharidosis (MPS) I–IV (Hurler disease, Hunter disease, Sanfilippo disease, Sly disease), GM1 gangliosidosis, sialidosis II, Zellweger.

   Skin +/– connective tissue: homocystinuria; Menkes; fucosidosis; multiple sulphatase deficiency; galactosialidosis; prolidase deficiency.



Investigations for chronic encephalopathy


·  Clinical: developmental assessment and neurological examination


   Imaging: MRI of head; X-rays of hands, chest, lateral spine

   Blood: plasma amino acids; ammonia; lactate

   Urine: amino acids, organic acids, and mucopolysaccharide and oligosaccharide screen

   Electrophysiology: auditory brainstem reflexes; visual-evoked potentials; somatosensory-evoked potentials; nerve conduction;


Acute encephalopathy


Deterioration in level of consciousness resulting from IMD:


may occur in a previously healthy child;


usually shows no focal features, but ataxia may be present;


may start with unusual behaviour;


·progresses rapidly, even to the stage of coma.


The likely causes are: hyperammonaemia; amino aci-dopathy; organic aciduria; fatty acid oxidation defect; mitochondrial defect; hypoglycaemia.




The IMD associated with stroke or stroke-like episodes are:



Fabry disease.


Organic acidopathy: methylmalonic acidaemia; propionic acidaemia; isovaleric acidaemia; glutaric aciduria I and II.


Ornithine transcarbamoylase deficiency.




Congenital disorder of glycosylation type 1A.


Familial hemiplegic migraine.


Movement disorder


Ataxia: maple syrup urine disease; pyruvate dehydrogenase deficiency; Friedreich ataxia; abetalipoproteinaemia.

Choreoathetosis and dystonia: glutaric aciduria I; Lesch–Nyhan disease; triose phosphate isomerase deficiency.

Parkinsonism: Wilson disease; tyrosine hydroxylase deficiency.




Acute intermittent muscle weakness: hyperkalaemic periodic paralysis; paramyotonia congenita; hypokalaemic periodic paralysis.


·Progressive muscle weakness: glycogen storage disease II (GSD, Pompe disease); GSD III.


Exercise intolerance with cramps and myoglobinuria: myophosphorylase deficiency, carnitine palmitoyltransferase II.

Myopathy as a manifestation of multisystem disease: mitochondrial myopathies.


Autonomic dysfunction 

The causes include: dopamine B-hydroxylase deficiency; neurovisceral porphyrias; Fabry disease; MPS I–III; occipital horn syndrome; mitochondrial neurogastrointestinal encephalomyopathy.


Psychiatric problems


The causes include the following:

Child: MPS II; MPS III; X-linked ALD; Lesch–Nyhan syndrome.


Adolescent: late-onset MLD; late-onset GM2 gangliosidosis; porphyria; Wilson disease; Wolfram syndrome; cerebrotendinous xanthomatosis; urea cycle defect; homocystinuria; adult onset neuronal ceroid lipofuscinosis.


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