Paediatrics: Metabolic syndromes: neurological

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;

EMG; EEG

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.

Stroke

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

• Homocystinuria.

• Fabry disease.

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

• Ornithine transcarbamoylase deficiency.

• MELAS

• 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.

Myopathy

• 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.