Table 4.
Details of IEM cases with negative specialized metabolic testing.
| Diagnosis | Specialized metabolic testing results | Clinical features | Imaging | Method of Diagnosis |
|---|---|---|---|---|
| Lipoic acid synthase deficiency | Urine OA, ammonium, carnitines = normal. Plasma AA initially elevated glycine but normalized on repeat testing. Urine sulfites, normal. No TSH, VLCFA. | Refractory neonatal seizures, imaging consistent with HIE but history not in keeping | HUS ‐ symmetric increased WM echogenicity, cystic changes in caudothalamic grooves; MRI‐diffuse WM signal abnormalities and diffusion restriction | WES (expedited due to acuity): lipoid acid synthase deficiency |
| Smith Lemli Opitz syndrome | Urine OA, ACP, carnitines, serum AA, homocysteine, MPS, CDG, biotinidase, folate, ammonia = normal | Hypotonia, feeding difficulties, GDD, dysmorphic features | MRI‐ low brain volume, mild delay in myelination | WES (two pathogenic mutations in DHCR7 gene) |
| Glycogen storage disease 3a | Urine OA normal; carnitines, ACP, serum AA, urine AA normal | Recurrent episodes of ketotic hypoglycemia, hepatomegaly, encephalopathy/ irritability/ inconsolability | None | multi gene panel (homozygous deletion in AGL gene) |
| Phosphoglycerate dehydrogenase deficiency | Serum AA, urine OA = normal | Significant microcephaly, increased appendicular tone, mild dysmorphic features | MRI simplified gyro pattern on MRI with delayed myelination, thin CC | WES (homozygous pathogenic mutation in PHGDH gene) |
| Glycogen storage disease 9 | Urine OA, carnitines, ACP, quant AA, ammonium = normal | Ketotic Hyoglycemic episodes, poor growth, GDD | None |
Targeted testing (sibling diagnosed by WES) (mutation in PHKA2 gene) |
| Lesch‐Nyhan syndrome | Plasma AA, urine OA, MPS, CK normal | Profound axial hypotonia, GDD. Consanguineous parents | MRI showed prominence of CSF spaces suggestive of EVOH |
WES (HPRT1 pathogenic variant) |
| Krabbe disease | Ammonium, CDG, carnitines, pyruvate, plasma AA, urine OA, ACP, creatine disorders panel, urine oligosacch, urine MPS, urine AA = normal | Developmental regression (severe), abnormal posturing + hypertonia | MRI brain suggestive of leukodystrophy in keeping with Krabbe | Galactocerebrosidase activity low (0.6). Genetic testing for GALC gene (pathogenic homozygous variant) |
AA, amino acids; ACP, acylcarnitine profile; CC, corpus callosum; CDG, congenital disorder of glycosylation; EVOH, ex vacuo hydrocephalus; MPS, mucopolysacchridoses; OA, organic acids; TSH, thyroid stimulating hormone; VLCFA, very long chain fatty acids.