National Metabolic Biochemistry Network Best Practice Guidelines. The Biochemical Investigation of Fits and Seizures for Inherited Metabolic Disorders

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1 Introduction National Metabolic Biochemistry Network Best Practice Guidelines The Biochemical Investigation of Fits and Seizures for Inherited Metabolic Disorders These guidelines describe the differential diagnosis of biochemical causes of severe neurological crises presenting as fits/seizures. They suggest an approach to diagnosis but do not include an exhaustive list of all possible defects. It is useful to note that fits may well be associated with febrile disorders but intercurrent illness can also provoke a metabolic crisis in affected children. This is frequently the case for disorders of fatty acid oxidation. However it is important to appreciate that between 2 and 5% of the general population suffer from some limited form of epilepsy. Whilst there is commonly an hereditary basis, monogenic disorders together form a small subset of less than 30%. The most common group of inherited epilepsies are the channelopathies. Many mutations have been identified in genes associated with Na and K ion channels. The Guidelines Clinical history, take careful note of age at onset, prematurity or birth trauma, infections, intercurrent illness, therapy especially chemotherapy or valproate, severity, EEG changes, family history. Seizures are a secondary phenomenon in many serious metabolic disturbances. Note particularly any evidence of hypoglycaemia, hypocalcaemia, metabolic acidosis or hyperammonaemia. If present then follow relevant investigation protocol see separate guidelines. First Line Investigations These are essentially the starting point for investigating potential metabolic disturbances:- sodium, potassium and calcium (plasma) blood gases blood/plasma ammonia urine amino and organic acids bloodspot acyl carnitines plasma and CSF lactate and amino acids urate (plasma) 1

2 Second Line Investigations When nothing helpful has been forthcoming from the initial tests but the symptoms persist and there is still concern about the possibility of a metabolic disorder, further investigations should be considered. These investigations may also be indicated at outset if there are specific clinical signs (see Table). The age at presentation is a guide only - considerable overlap is observed in practice. Please note; It would be likely that at this stage a panel of leucocyte enzymes would be tested to exclude/diagnose lysosomal storage disorders. This should include α- and β- mannosidosis, α-fucosidosis, α-neuraminidase (sialidosis), β- galactosidase (GM1 gangliosidosis) and β-hexosaminidase (Tay-Sachs disease) The following list does not contain the disorders that should have been detected via the first line investigations outlined above, e.g. urea cycle defects and organic acidurias. For further information about the availability or sample requirements for individual tests access the Metabolic Assay Directory on the MetBionet website ( Author Dr Mick Henderson, Department of Clinical Biochemistry, Leeds Teaching Hospitals Trust, mick.henderson@leedsth.nhs.uk Further reading: Noebels JL. The Inherited Epilepsies, in The Metabolic and Molecular Bases of Inherited Disease. Ed Scriver CR et al. 8th ed pp Physician s Guide to the Laboratory Diagnosis of Metabolic Diseases. N. Blau, M. Duran, M.E. Blaskovics and K.M. Gibson Ed.s. 2 nd edn 2002 Springer-Verlag, Berlin Bernard BS and Lowenstein DH. Mechanisms of Disease; Epilepsy. NEJM 2003,349;13, Version Number 04 Review date Sept 2012 Disclaimer These are laboratory guidelines reflecting current best practice in specialist metabolic laboratories the UK. They are not evidence based but reflect expert opinion. The network cannot accept any responsibility for use of these guidelines. 2

3 Disorder Neonatal/early onset Supporting Clinical Signs Presentation Test Peroxisomal defects of β-oxidation and organelle genesis dysmorphism, hypotonia, liver dysfunction plasma very long chain fatty acids Biotinidase alopecia, skin rashes, plasma biotinidase hypotonia Non ketotic hyperglycinaemia hypotonia, apnoea, burstsuppression plasma and CSF glycine EEG 3-Phosphoglycerate dehydrogenase microcephaly, plasma and CSF serine psychomotor retardation Molybdenum cofactor lens dislocation urine and plasma low urate urine and plasma sulphocysteine undetectable plasma homocysteine isolated sulphite oxidase lens dislocation urine and plasma sulphocysteine undetectable plasma homocysteine Glutaric acidaemia type 1 macrocephaly, dystonia urine organic acids and bloodspot acylcarnitines are not always positive, It may be necessary to assay the enzyme in cultured fibroblasts GLUT 1 Homocystinuria, remethylation defects γ-aminobutyrate transaminase Aromatic amino acid decarboxylase Pyridoxine responsive seizures Pyridoxal Phosphate responsive seizures Pterin Disorders Tyrosine hydroxylase Slow head growth, micocephaly hypotonia, micocephaly psychomotor retardation, hypotonia mental retardation, hypotonia, recurrent hyperthermia, hypersalivation, bulbar symptoms, temperature instability responds to pryidoxine may take up to four weeks pyridoxine unresponsive but responds to pyridoxal phosphate mental retardation, hypotonia, recurrent hyperthermia, hypersalivation, bulbar symptoms. oculogyric crises, CSF glucose (low) (ratio to plasma) plasma total homocysteine CSF GABA* Urine vanilylactic acid increased CSF Neurotransmitters, HVA, HIAA and dopamine low * Linked to mutations in antiquitin gene. Can be diagnosed by measuring urine AASA (alpha amino adipic semi aldehye), will also have urine vanillactic acid increased. CSF neurotransmitters, HVA, HIAA and dopamine low * incr gly and threo and his Urine vanillactic acid increased CSF Neurotransmitters, HVA, HIAA and dopamine low * incr gly and threo and his. urine AASA not increased quantitative plasma phenylalanine CSF pterins* erythrocyte DHPR plasma and urine pterins CSF Neurotransmitters* Low HVA 3

4 Menkes syndrome (X-linked) Later infancy/early childhood Purine and pyrimidine disorders Carbohydrate deficient glycoprotein disorders CLN 1,2 (Batten s Disease) Creatine synthesis disorders - (GAMT) Guanidinoacetate Methyltransferase - (AGAT) Arginine:glycine amidinotransferase Creatine transporter defect Respiratory chain defects Niemann-Pick disease type C Parkinsonian symptoms, hypotonia, Kinky hair hypothermia Developmental delay Presentation Psychomotor retardation, Cerebellar hypoplasia, Microcephaly, feeding difficulties unusual distribution of sub cutaneous fat, strokes, ataxia, atrophy of cerebellum, clotting abnormalities. dysmorphism. visual loss, retinitis pigmentosa, dementia mental retardation, speech delay, extrapyramidal symptoms Mental retardation, speech delay hypotonia, ptosis. brain stem abnormalities. hepatosplenomegaly. supranuclear ophthalmoplegia plasma copper and caeruloplasmin urine purines and pyrimidines plasma transferrin isoforms CLN1 leucocyte palmitoyl protein thioesterase CLN2 leucocyte tripeptidyl peptidase I skin biopsy may be necessary low plasma and urine creatinine. Definitive test is brain MRS for creatine. Plasma and urine guanidinoacetate elevated in GAMT and reduced in AGAT. Definitive test is brain MRS for creatine Increased creatine:creatinine ration in urine may have elevated plasma lactate but lactate accumulation can be confined to CNS, i.e. elevated CSF lactate. Muscle biopsy. Plasma chitotriosidase (nonspecific), Fibroblast filipin staining and/or cholesterol esterification Gaucher type 2 hepatosplenomegaly Plasma chitotriosidase (nonspecific). Leucocyte betaglucosidase Later childhood in addition to the above Gaucher disease type 3 Lafora disease Disorders of folate metabolism CLN3 (Juvenile Battens Disease) Acute porphyrias hepatosplenomegaly, dystonia. intellectual decline and early death Visual loss, retinitis pigmentosa, dementia Presentation usually after puberty, acute abdomen, pyschosis Plasma chitotriosidase (nonspecific). Leucocyte betaglucosidase demonstration of storage material in tissue biopsy discuss with your specialist laboratory see metabolic assay directory DNA analysis for common deletion. Urine PBG 4

5 * Before sample collection and storage refer to CSF instruction sheet from The Neurometabolic Unit, National Hospital for Neurology and Neurosurgery, London UK. A copy is available from the MetBioNet website 5