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Supplementary Table 1. Biochemical/Metabolic Disorders in ICEE; Clinical Features and Relevant Diagnostic Tests

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Supplementary Table 1. Biochemical/Metabolic Disorders in ICEE; Clinical Features and Relevant Diagnostic Tests BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Arch Dis Child Educ Pract Ed Supplementary table 1. Biochemical/metabolic disorders in ICEE; clinical features and relevant diagnostic tests: Presentation Age of </> 1 year of Disorder group Disorder Sub disorder onset age Other features Treatable? Test Often infants born prem, sometimes family history of < 3 infertility & recurrent CSF pyridoxal Vitamin B6 PNPO months <1y miscarriage. Yes phosphate (UOA) Metabolic acidosis, electrolyte disturbance, abdominal distension, and feed intolerance, CSF pipecolate (pre- resulting in misdiagnosis as treatment); (urine Pyridoxine responsive < 3 hypoxic–ischaemic AASA where epilepsy months <1y encephalopathy or sepsis. Yes available) Failure to thrive & multisystem disease in early infancy; Congenital disorders of </> 3 hypotonia and seizures can glycosylation. Many subtypes months </> 1y be part of the clinical picture. most not Transferrin glycoforms Methylmalonic </> 3 Acute metabolic Organic acidurias acidurias months </> 1y decompensations. Yes UOA / acylcarnitines </> 3 Acute metabolic Propionic acidaemia months </> 1y decompensations. Yes UOA / acylcarnitines Developmental delay, hypotonia, dysmorphic D-2-hydroxyglutaric </> 3 features, often with aciduria months </> 1y cardiomyopathy. No UOA L-2-hydroxyglutaric > 3 aciduria months </> 1y Cerebellar dysfunction. Yes UOA Severe muscle weakness, respiratory distress Combined L and D < 3 syndrome, lack of 2OH-glutaric aciduria months <1y psychomotor development. No UOA Perry LD, et al. Arch Dis Child Educ Pract Ed 2021;0:1–8. doi: 10.1136/archdischild-2020-320606 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Arch Dis Child Educ Pract Ed Supplementary table 1. Biochemical/metabolic disorders in ICEE; clinical features and relevant diagnostic tests: Hypotonia or spasticity, delayed psychomotor 3-methylglutaconic < 3 development, intellectual aciduria type Ix months <1y disability. No UOA </> 3 Deafness, encephalopathy MEGDEL months </> 1y and Leigh-like syndrome. No UOA 3-methylcrotonyl-CoA > 3 > 1y carboxylate deficiency (Types 1 & 2) months (majority) Metabolic decompensation. Partially UOA / acylcarnitines Aminoacylase 1 </> 3 Wide phenotypic deficiency months </> 1y heterogeneity. No UOA Developmental delay and neuro-regression, prominent pyramidal and extra- pyramidal signs, orthostatic </> 3 acrocyanosis, petechiae, EMA encephalopathy months <1y severe diarrhoea. Yes UOA Developmental delay, hypotonia, mental retardation, ataxia, hyperkinetic 4-hydroxybutyric > 3 behaviour, aggression, sleep aciduria months >1y disturbances. No UOA Hypotonia, profound psychomotor retardation, and brain abnormalities, such as agenesis of the corpus callosum, gyral defects, and ventriculomegaly. Many patients show neonatal distress, metabolic acidosis, and/or encephalopathy. Older children less likely to have </> 3 epilepsy & brain Fumarase deficiency months </> 1y malformations. No UOA Glutaric aciduria type > 3 Gliosis and neuronal loss in UOA / acylcarnitines / 1 months </> 1y the basal ganglia, progressive Yes New-born screening. Perry LD, et al. Arch Dis Child Educ Pract Ed 2021;0:1–8. doi: 10.1136/archdischild-2020-320606 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Arch Dis Child Educ Pract Ed Supplementary table 1. Biochemical/metabolic disorders in ICEE; clinical features and relevant diagnostic tests: movement disorder / Macrocephaly / acute metabolic decompensations. </> 3 Severe mental retardation, D-glyceric aciduria months <1y microcephaly. Yes UOA Multiple acyl-CoA Acute metabolic dehydrogenase < 3 decompensations, +/- deficiency months <1y congenital anomalies. Yes UOA / acylcarnitines Ataxia, hypotonia, encephalopathy, and skin manifestations including alopecia and a generalized or Multiple carboxylase / </> 3 perioral biotinidase deficiency months </> 1y eczematous rash. Yes Biotinidase & UOA Coarsening facial features, and usually hepato(spleno)megaly. Cherry-red spot & dysostosis. Seizures are a > 3 major part of the progressive Leucocyte beta- Lysosomal GM1 gangliosidosis months </> 1y neurological dysfunction. No galactosidase Leucocyte </> 3 late infantile Extreme irritability, spasticity, galactocerebrosidase Krabbe months >1y developmental delay. No activity SGA, extrapyramidal signs (truncal hypotonia, dystonia, BH4-deficient chorea), swallowing Amino acids Phenylalanine hyperphenylalaninaemia <1y difficulties. Intellectual disability, “mousy” > 3 odor, light pigmentation, Phenylketonuria months <1y eczema. Yes Plasma amino acids seizures that are > 3 usually precipitated by Proline Hyperprolinaemia type 2 months >1y infection and fever Possibly Plasma amino acids Perry LD, et al. Arch Dis Child Educ Pract Ed 2021;0:1–8. doi: 10.1136/archdischild-2020-320606 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Arch Dis Child Educ Pract Ed Supplementary table 1. Biochemical/metabolic disorders in ICEE; clinical features and relevant diagnostic tests: glycine encephalopathy - lethargy, encephalopathy, (aka non-ketotic < 3 atypical profound hypotonia, and CSF glycine (+ paired Glycine hyperglycinaemia) months forms later hiccoughs. No plasma AA) global developmental delay, Adenosine kinase <3 early-onset seizures, mild Plasma AA (Raised Methionine deficiency months <1y dysmorphic features No methionine) phosphoglycerate Congenital or acquired dehydrogenase <3 microcephaly. hypertonia & CSF serine (+ plasma Serine deficiency months <1y severe developmental delay Possibly AA) Maple syrup urine </> 3 Acute metabolic Plasma AA (UOA) / Branched chain AA disease months </>1y decompensations Yes new-born screening. < 3 CPS deficiency, NAGS months Urea cycle deficiency (usually) </>1y Sometimes NH3 and plasma AA </> 3 Encephalopathy, cerebral NH3 and plasma AA, oedema-associated OTC deficiency months </>1y Yes urine orotate respiratory changes, </> 3 hepatomegaly argininosuccinic aciduria months </>1y Yes NH3 and plasma AA </> 3 citrullinaemia months </>1y Yes NH3 and plasma AA </> 3 Loss of milestones, spasticity, NH3 and plasma & HHH months </>1y DD and growth Yes urine AA </> 3 Arginase deficiency months </>1y Spastic quadriplegia Yes NH3 and plasma AA life-threatening metabolic crisis, with hyperammonaemia, Carbonic anhydrase </> 3 hyperlactataemia, and NH3 / plasma AA deficiency months </>1y ketonuria Yes /UOA Very rare: encephalopathy, Congenital glutamine < 3 lack of normal development, deficiency months <1y seizures, and hypotonia No Plasma AA Perry LD, et al. Arch Dis Child Educ Pract Ed 2021;0:1–8. doi: 10.1136/archdischild-2020-320606 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Arch Dis Child Educ Pract Ed Supplementary table 1. Biochemical/metabolic disorders in ICEE; clinical features and relevant diagnostic tests: associated with variable brain abnormalities developmental regression ⁄ > 3 dementia, and pigmentary White cell PPT, TPP1 Battens Multiple subtypes months </>1y retinopathy. CLN2 only detects CLN1 & 2 only Adenylosuccinase </> 3 Hypotonia, sometimes IUGR Urine Purines deficiency months </>1y & microcephaly No purines/pyrimidines dihydropyrimidine dehydrogenase > 3 Phenotypically (UOA) & deficiency months </>1y heterogeneous No purines/pyrimidines dysmorphic features, ERG frequently markedly reduced /absent. Punctate calcification of cartilage, small renal cysts may be apparent on ultrasound, Zellweger syndrome / and LFTs may be abnormal, peroxisome biogenesis </> 3 sometimes with clinical Peroxisomal defects months </>1y jaundice. VLCFA > 3 Small no of boys Px with Adrenoleukodystrophy months >1y seizures first Possible VLCFA 2,4-dienoyl-CoA <3 Plasma amino acids, Fatty acid oxidation reductase deficiency months <1y n = 2 No acylcarnitines, lactate Neurodegeneration due to cerebral folate > 3 irritability & WM abnormalities Yes - Folate deficincy months >1y on brain MRI reversible CSF MTHF dihydrofolate > 3 megaloblastic anaemia or Yes - reductase deficiency months >1y pancytopenia reversible CSF MTHF > 3 Yes - FOLR mutations months >1y progressive ataxia reversible CSF MTHF Typically, of multiple seizure Plasma and urine > 3 types. Movement disorder in guanidinoacetate and Creatine GAMT deficiency months >1y adolescence Yes creatine Perry LD, et al. Arch Dis Child Educ Pract Ed 2021;0:1–8. doi: 10.1136/archdischild-2020-320606 BMJ Publishing Group Limited (BMJ) disclaims all liability and responsibility arising from any reliance Supplemental material placed on this supplemental material which has been supplied by the author(s) Arch Dis Child Educ Pract Ed Supplementary table 1. Biochemical/metabolic disorders in ICEE; clinical features and relevant diagnostic tests: mental retardation, severe Creatine transporter </> 3 speech delay, behavioural defect months </>1y abnormalities, and seizures Yes Urine creatine cyanotic attacks or of eye movement seizures which </> 3 may be mistaken for CSF/plasma glucose Glucose transport GLUT-1 months </>1y opsoclonus–myoclonus Yes ratio Molybdenum cofactor / Sulfite oxidase < 3 dystonia and developmental Urine sulphocysteine deficiency months <1y delay Possibly (urine purines) plasma and CSF Pyruvate dehydrogenase </> 3 Leigh syndrome (girls with Yes, lactate, fibroblast PDH Mitochondrial disease Numerous deficiency months </>1y West syndrome) sometimes activity Perry LD, et al. Arch Dis Child Educ Pract Ed 2021;0:1–8. doi: 10.1136/archdischild-2020-320606.
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