Table 4.

IEMs identified by Tier 2 diagnostic tests.

Diagnostic test	Related treatable IEM	Related non-treatable IEM
Blood smear		Juvenile neuronal ceroid lipofuscinosis, GM1 gangliosidosis, Salla disease, fucosidosis (vacuolated lymphocytes)
Carbohydrate-deficient transferrin		Disorders of glycosylationfeat: Intellectual disability, ataxia, inverted nipples, abnormal fat pads.
Leukocyte CoQ10	Primary CoQ10 deficiency feat: Encephalomyopathy, nephrotic syndrome, hearing loss, cerebellar ataxia.
Blood Enzyme Activity: •Glucocerebrosidase •Arylsulfatase-A •Biotinidase •PPT1/TPP1	Metachromatic leukodystrophy feat: Dementia, psychosis/(manic-) depression, behavioral disturbance, spasticity, neuropathy. Biotinidase deficiency feat: Encephalopathic crisis, sensorineural hearing loss, eczema, alopecia.	Gaucher disease type 3 feat: Dementia, horizontal supranuclear gaze palsy. Epilepsy.Neuronal ceroid lipofucinosis feat: accumulation of autofluorescent ceroid lipopigments, retinal pathology leading to blindness, dementia, epilepsy.
Very long chain fatty acids		X-linked adrenoleukodystrophyfeat: cognitive deficits, progressive demyelination of CNS, visual loss, sensorineural deafness, convulsions and dementia.Peroxisomal biogenesis disorder (Zellweger spectrum)feat: developmental delay, hypotonia, vision problems, hearing loss, liver dysfunction, renal cysts, epiphyseal stippling, demyelination.
Urine oligosaccharides		GM2 gangliosidosis (Tay-Sachs disease, Sandhoff disease)feat: cherry-red spot, hypotonia, hepatosplenomegaly, ataxia, myoclonus, spastic tetraparesis, decerebrationSialidosisfeat: Type I: cherry-red spot, myoclonus syndrome (responds to alcohol), gait abnormalities, epilepsy. Type II: progressive psychomotor decline, facial dysmorphism, myoclonus, kyphosisAspartylglucosiminuriafeat: slowly developing mental decline, beginning with clumsiness, late speech, hyperkinesia, mild facial dysmorphism, slight kyphoscoliosis
Urine sialic acid		Salla diseasefeat: Hypotonia, progressive neurodegeneration, hypomyelination.
Urine sulfocysteine		Molybdenum cofactor and isolated sulfite oxidase deficienciesfeat: epileptic encephalopathy, lens dislocation, hyperekplexia, multicystic encephalomalacia.
CSF:plasma glucose ratio	GLUT1 deficiency feat: Ataxia, cerebral atrophy, epilepsy, non-epileptic movement disorder.
CSF lactate/pyruvate	GLUT1 deficiency	Mitochondrial disorders
CSF amino acids	Serine biosynthesis disorders feat: Epilepsy, neuropathy, cerebral atrophy, microcephaly, ichthyosis. Severe forms with Neu-Laxova syndrome.	Nonketotic hyperglycinemia feat: apnea, corpus callosum dysgenesis, epilepsy.Glutamine synthetase deficiencyfeat: epileptic encephalopathy, delayed gyration, necrolytic erythemaAsparagine synthetase deficiencyfeat: epileptic encephalopathy, spastic quadriplegia, microcephaly, hyperekplexia.
CSF biogenic amines and BH4	Tetrahydrobiopterin deficiencies •DHPR deficiency: Developmental delay, epilepsy, microcephaly, Parkinsonism, cerebral atrophy and basal ganglia calcifications. •AR GTPCH deficiency: Developmental delay, epilepsy, microcephaly, truncal hypotonia, limb hypertonia. •PTPS deficiency: Developmental delay, epilepsy, microcephaly, Parkinsonian dystonia, lethargy, autonomic dysfunction. Tyrosine Hydroxylase deficiency feat: dystonia, postural tremor, developmental and motor delay, limb rigidity, hypokinesia, ptosis and oculogyric crisis.
	AADC deficiency Developmental delay, hypotonia, autonomic symptoms, non-epileptic movement disorder, oculogyric crises, epilepsy.
CSF tetrahydrofolate	FOLR1 deficiency feat: psychomotor decline, epilepsy with drop attacks, progressive movement disorder, hypomyelination. MTHFR deficiency feat: developmental delay, hypotonia, apnea, epilepsy, thrombosis, brain atrophy. DHFR deficiency feat: megaloblastic anemia, seizures. Serine biosynthesis disorders feat: Microcephaly, developmental delay, spasticity, seizures, neuropathy, ichthyosis.