| Blood Biochemistry | |||
| Test | Indications | Precautions | Interpretation |
| α-AASA | Neonatal epileptic seizures (usually with burst-suppression) and any unexplained refractory epilepsy up to the age of 2 years at onset | Supports a diagnosis of pyridoxine-dependent epilepsy (PDE) due to α-AASA-dehydrogenase deficiency | |
| Acylcarnitines | Acute metabolic encephalopathy. Acute myopathy, rhabdomyolysis. Unexplained hyperCKaemia | Specific acylcarnitines indicate particular disorders, e.g. octanoyl carnitine in MCAD deficiency, glutaryl carnitine in GA1, propionyl carnitine in cobalamin disorders | |
| Albumin | Suspect multisystem disorder (mitochondrial peroxisomal, congenital defect of glycosylation) | Discussion with laboratory may be necessary on techniques of albumin estimation | ↓ albumin may be the earliest clue to liver involvement in mitochondrial disorders such as with POLG1 mutations |
| Part of investigation of CSF in immunological abnormality | Allows calculations of CSF/serum albumin index, IgG albumin ratio and IgG index | ||
| Alpha-1 antitrypsin | Late neonatal intracranial haemorrhage | ↓ may be alpha-1-antitrypsin deficiency with PiZZ or PiSZ phenotype. ('Clotting screen' abnormal) | |
| Alpha-fetoprotein | Ataxic 'cerebral palsy'. Any type of movement disorder in early childhood. 'Oculomotor apraxia' (saccadic impairment) | ↑ in ataxia-telangiectasia, ataxia-oculomotor apraxia 2 (AOA2) and DGUOK deficiency (hepatocerebral form of mtDNA depletion) | |
| Amino acids | Learning disability. Hypotonia. Early-onset epileptic seizures including spasms. Acute encephalopathy. Intermittent ataxia. Acquired or progressive dystonia (NB consider BH4deficiency). Arterial ischaemic stroke | Deproteinize plasma promptly if homocystinuria is a possibility (see also homocysteine). Negative in homocystinuria after small dose of ingested pyridoxine. Not helpful for serine synthesis defects - need CSF | Aminoacidopathies (e.g. PKU, homocystinuria, glycine encephalopathy). Clue to early diagnosis of pyridoxal phosphate-responsive epilepsy and mitochondrial disorders. ↑ alanine may indicate chronic pyruvate accumulation |
| Ammonia (see also Ischaemic forearm test at end of this chapter) | Neonatal seizures ± vomiting. Acute encephalopathy. Vomiting-headache-impaired consciousness complex. 'Stroke'. Intermittent ataxia | May be fasting or postprandial or at time of acute illness. Can be venous or arterial but with minimum disturbance. Separate immediately | Normal arterial level is higher than venous. ↑ in urea cycle defects. Some organic acidurias. Reye syndrome, sodium valproate therapy, decompensated fatty acid disorders, illness with shock |
| Bile acids | Peroxisomal phenotype -see text | ↑ in various peroxisomopathies | |
| Biotinidase | Neurological deterioration ± myelopathy ± skin rash ± alopecia. Remission on biotin trial (see Chapter 2.16) | Serum (assay not affected by coincident biotin therapy). Expected organic aciduria may be subtle | ↓ in biotinidase deficiency |
| Ceruloplasmin (copper oxidase) | Early seizures, hypotonia, steely hair | ↓ in Menkes disease (unreliable in first weeks) | |
| Movement and/or behaviour disorder 5 years or older | ↓ in Wilson disease (not always) | ||
| Calcium | Neonatal seizures. Unexplained seizures ± photophobia, learning disability. Acquired dyskinesia. Basal ganglia calcification | ↓ in hypoealcaemia, true and pseudohypoparathyroidism, DiGeorge syndrome | |
| Developmental delay ± elfin face | ↑ in diopathic hypercalcaemia, Williams syndrome | ||
| Carnitine | Acute unexplained encephalopathy. Coma on valproate. Lipid and other acute myopathies | ↓↓ in primary carnitine transport defect. ↓ in various fatty acid oxidation disorders. (Valproate may be associated with carnitine depletion) | |
| Cholestanol | Learning disability, juvenile cataracts, limb pains | ↑ in cerebrotendinous xanthomatosis | |
| Cholesterol | Developmental delay with retinopathy and sensorineural deafness. Skeletal dysplasias. Ataxia especially with oculomotor apraxia. Spinocerebellar ataxia | Fasting | ↓ in peroxisomal deficiency, Smith-Lemli-Opitz syndrome and other defects of cholesterol biosynthesis, and abetalipoproteinaemia. ↑ in ataxia-oculomotor apraxia type 1 (A0A1) |
| Copper | Steely hair, early seizures | Ensure apparatus is completely copper free and avoid copper contamination | ↓ in Menkes disease (unreliable in first weeks) |
| Movement disorder ± behaviour disorder age 5 years or over | ↓ in Wilson disease (not always) | ||
| CoQ10 | Suspect mitochondrial disorder | White cells necessary | ↑ in ubiquinone deficiency |
| Creatine kinase | Expressive spEEGh delay, toe walking, acquired muscle weakness in a boy. Neonatal and infantile weakness in boys and girls | Test with minimal disturbance, preferably not after exercise or biopsy. HyperCKaemia is sometimes unexplained but many causes | ↑↑ in Duchenne and Becker muscular dystrophies ± ↑ in manifesting carriers. ↑ in other dystrophies, esp. a-sarcoglycan and caveolin3 (CAV3) mutations. ↑ or ↑↑ in VLCAD, LCHAD, MADD/GA2, CPTII, myophosphorylase and myoadenylate deaminase deficiencies, ryanidine receptor (RYR) mutations and other malignant hyperthermias, usually provoked. ↑ extreme exertion, dyskinesia, low T4, mitochondrial. ↑ in congenital muscular dystrophy (often), myositis (often) |
| Creatinine | Learning disability, epileptic seizures and movement disorder | ± ↓ in GAMT and AGAT deficiency | |
| DHAP-AT | Peroxisomal phenotype | ↓ in all cases of reduced peroxisome number | |
| 7-dehydrocholesterol | Suggestive dysmorphism | ↑ in Smith-Lemli-Opitz syndrome | |
| Electrolytes (sodium/ potassium chloride/ bicarbonate) | (Any acute illness.) Paroxysmal weakness | Potassium abnormalities in various periodic paralyses | |
| Endocrine (Cortisol, insulin etc.) | Hypoglycaemia, may be epileptic seizures | Low Cortisol may indicate reduced ACTH responsiveness | |
| Ferritin (↓ iron deficiency) | 'Seizures' | ↓ neurally mediated syncope | |
| Unpleasant urge to move legs, relieved by sleep | ↓ restless leg syndrome | ||
| 'Infection' | ↑ familial haemophagocytie lymphohistiocytosis | ||
| Glucose | Reduced consciousness level. Epileptic seizures | In fasting test do blood levels immediately before lumbar puncture | Various hypoglycaemic situations. Normal blood glucose with ↓ CSF glucose may indicate GLUT1 deficiency |
| GTP cyclohydrolase-1 (GCH1) | Dopa-responsive dystonia and infantile dyskinesia/ parkinsonism with oculogyric crises | Estimated in mononuclear cells from peripheral blood -discuss with lab | ↓ in Segawa disease and in autosomal recessive GCH1 deficiency |
| Hexosaminidase A and B (free) | Wide neurological phenotype | Serum or plasma, ± 'low' in normal children | i in Sandhoff disease or juvenile Sandhoff disease |
| Homocysteine (total plasma homocysteine) | Neonatal hypoxic-ischaemic encephalopathy without convincing history | More sensitive than urine sulphite test | ↑ sulphite oxidase deficiency |
| Homocysteine (total plasma homocysteine) | Arterial ischaemic stroke. 'Psychiatric' myelopathy | B<sub<12< sub="> may be normal in genetic cobalamin defects | ↑ in homocystinuria, MTHFR deficiency, cobalamin disorders |
| Lactate (see also Ischaemic forearm test at end of this chapter) | Acute encephalopathy (± ↑ anion gap). Suspect mitochondrial disorder. Intermittent ataxia/ movement disorder. Organic aciduria. Hypoglycaemia | Minimal disturbance of child (ideally collect sample 30min after placing i.v. catheter) and immediate processing of specimen. May be random or 1h before or 1h after feed | ↑ in a wide range of disorders, in particular mitochondrial respiratory chain deficiencies |
| Lysosomal enzymes | Various dysmorphisms, coarse facies, hepatosplenomegaly, developmental regression | Know what is being tested for. Beware inferences from 'heterozygous' levels and pseudo-deficiencies. Pay attention to substrate used and note that activator protein deficiency may cause typical disease with normal enzyme levels | Specific enzyme deficiency confirms specific targeted diagnosis, e.g. Krabbe disease, metachromatic leukodystrophy, etc. |
| Magnesium | Neonatal seizures | ↓ in disturbances of magnesium metabolism | |
| Manganese | Movement disorder, polycythaemia, liver cirrhosis. Brain MRI: manganese in basal ganglia | ↑↑ in novel very rare treatable autosomal recessive disorder | |
| Phosphate | Tetany, occasional epileptic seizure. Basal ganglia ± white matter calcification | Urine study required when renal tubular function is being tested | ↑ in hypoparathyroidism |
| Phytanic acid | Peroxisomal phenotype. Demyelinating neuropathy | Diet dependent | ↑ in various peroxisomopathies including Refsum disease |
| Pipecolic acid | Neonatal or later onset epilepsy responsive to either pyridoxine (PDE) or pyridoxal phosphate | No need to stop pyridoxine treatment | ↑ in PDE with a-amino adipic semialdehyde dehydrogenase deficiency |
| Peroxisomal-type dysmorphism | ↑ in peroxisomal and related metabolic disorders including GA2 | ||
| Prolactin | Unexplained 'convulsions' | Timing important | ↑ after both epileptic seizures and syncopes but not after psychological events |
| Prolactin | Investigation of dopamine-related disorders | ↑ in dopamine deficiency disorders | |
| Pyruvate | As for blood lactate | Preferably 1h after a meal. Unstable: transfer within 30s to 8% perchlorate on ice | ↑ in defects of pyruvate dehydrogenase |
| Thiamine | Acquired neurological deficit such as oculomotor impairments and ataxia with bizarre history | Low in Wernicke encephalopathy | |
| Thyroid function tests | Typical hypothyroid phenotype | ↓ = hypothyroidism (including in Down syndrome and CDG1a) | |
| Hashimoto encephalopathy | Anti-thyroperoxidase +ve | May be euthyroid | |
| Hereditary chorea | ± ↓ with thyroid transcription factor (TITF-1) mutation | ||
| Free T3 (FT3) | X-linked learning disability with dystonic 'cerebral palsy' ± eye movement defect ± delayed myelination | ↑ free T3 due to monocarboxylate transporter 8 (MCT8) gene mutation (T4 often ↓) | |
| Transaminases | •Congenital infection-like' | Negative virology | ↑ Aicardi-Goutieres syndrome |
| Intractable partial seizures ± myoclonus ± acute encephalopathy | ↑ Alpers (POLG1) | ||
| Incidental finding | NB transaminases may come from muscle as well as liver | ↑ Muscular dystrophies | |
| Developmental delay with hypotonia | ↑ in other mitochondrial disorders and CDG | ||
| Transferrin (isoelectric focusing for sialotransferrin) | Delay, hypotonia, cerebellar hypoplasia/atrophy | Choose your laboratory. False negatives for CDG not uncommon especially in neonates and early childhood. False positives in galactosaemia and hereditary fructose intolerance | Abnormal in CDG especially type 1a |
| Urate | Early acquired movement disorder with motor delay | Urine urate is more reliable (better sensitivity) | ↑ in Lesch-Nyhan or similar disorder |
| Urate | Dysequilibrium-diplegia | ↓↓ in purine nucleoside phosphorylase deficiency | |
| Neonatal epilepsy with cerebral destructive lesions | ↓ in molybdenum cofactor deficiency (is normal in isolated sulphite oxidase deficiency) | ||
| Urea | Atypical headache often with recurrent impairment of consciousness. 'Stroke' | ↓ plasma urea may indicate urea cycle disorder including heterozygous (OTC) deficiency. ↑ in renal failure and gastrointestinal bleeds, any cause | |
| Very long-chain fatty acids (VLCFAs) | Suspect peroxisomopathy | Even though D-bifunctional protein (DBP) deficiency affects the VLCFA pathway, DBP deficiency cannot be exluded by normal plasma VLCFA: fibroblast studies needed | ↑ in most peroxisomal disorders including all global peroxisomal deficiencies |
| School-age regression | ↑ in adrenoleukodystrophy (ALD) | ||
| Vitamin A | Loss of vision in autism | ↓ with deficient diet | |
| Vitamin B12 | Developmental delay in a purely breast-fed infant ± seizures ± movement disorders | ↓ when mother on a vegan (or even a vegetarian) diet. Movement disorder may ↑ after B12 treatment of deficiency. Macrocytosis is not always present | |
| Vitamin E | Developmental delay, with retina! defect and sensorineural deafness, spinocerebellar ataxia ± retinitis pigmentosa | ↓ in some peroxisomal disorders, abetalipoproteinaemia, selective vitamin E malabsorption | |
| Abbreviations: CPTII = carnitine palmitoyl transferase II; DHAP-AT = dihydroxyacetone phosphate acyltransferase; LCHAD = long-chain 3-hydroxyacyl-coenzyme A deficiency; MADD/GA2 = multiple acyl-coenzyme A dehydrogenase deficiency/glutaric aciduria type 2; VLCAD = very-long-chain acyl-coenzyme A deficiency. | |||
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Biochemical investigations in Blood
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