Table 1.

Clinical and laboratory findings in amino acid synthesis disorders

Disorder	Clinical features	Biochemical /molecular diagnosis	Treatment	Response to treatment
Serine deficiency (3-PGDH, PSAT, PSP)	Lethal phenotype (Neu-Laxova)
	Severe IUGR, multiple congenital abnormalities, dysmorfic features, contractures, ptyrigium, syndactyly, neural tube defects	CSF serine not reported CSF glycine not reported	not reported	not reported
		Plasma serine not reported Plasma glycine not reported
	Skin: ichthyosis, collodion-like	Molecular testing in all patients
	MRI: atrophy, vertriculomegaly, lissencephaly, cerebellar hypoplasia, absence vermis
	Infantile phenotype (congenital) microcephaly, IUGR, intractable seizures, severe psychomotor retardation, spastic quadriplegia, cataracts,	CSF serine 6–11 μmol/L Reference 30–75 CSF glycine 1-normal μmol/L Reference 2–10	500mg/kg/day L-serine 200mg/kg/day glycine	Control of seizures or significantly lowered frequency, improvement of wellbeing. Increased white matter volume. No to limited effect on psychomotor development.
	Skin: not reported
	MRI: hypomyelination and delayed myelination, cerebellar abnormalities	Plasma serine 28–64 μmol/L, reference 85–235 Plasma glycine 128 μmol/L –normal, reference 145–420		Antenatal or presymptomatic treatment: prevention of neurological abnormalities
				Control of seizures, improvement of behaviour and school performance
		Urine not informative
	Juvenile phenotype Mild- moderate intellectual deficiency, absence seizures, behavioural problems		100-150mg L-serine /kg/day
		CSF serine 9 μmol/L Reference 20–45 CSF glycine normal Reference 2–10 Plasma serine 58,63 μmol/L reference 60–185 Plasma glycine normal Reference 125–365
	Skin: striae rubra
	MRI: no abnormalities
	Adult phenotype		120 mg L-serine /kg/day	Improvement in ADL activities
	Congenital cataract Psychomotor retardation Polyneuropathy, cerebellar ataxia and nystagmus	Urine not informative
		CSF serine 13 μmol/L Reference 15–50 CSF glycine normal Reference 2–10 Plasma serine 33 μmol/L Reference 65–170 Plasma glycine 93 μmol/L Reference 120–445
	Skin: not reported
	MRI: no abnormalities
	EMG: Charcot-Marie-Tooth type 2 polyneuropathy
Glutamine deficiency	Neonatal phenotype
	Respiratory insufficiency, hypotonia, neonatal seizures, cardiac failure, gastrointestinal symptoms	Plasma glutamine 2-6 μmol/L Reference 250–700 CSF glutamine 11–12 μmol/L reference 245–650 Urine glutamine ND-8	not possible
	Skin: epidermal necrolysis
	MRI: abnormal gyration, cortical and cerebellar atrophy, white matter abnormalities, germinolytic cysts
	Milder phenotype Severe psychomotor retardation, intractable seizures, spastic diplegia,		L-glutamine up to 1020 mg/kg/day	Improvement of alertness and EEG abnormalities. Partial correction of CNS glutamine deficiency
	Skin: necrolytic skin rash	Plasma glutamine 8–354 μmol/L reference 250–700 CSF glutamine 121 μmol/L reference 245–650
	MRI: hypomyelination, cortical atrophy, thin corpus callosum
Proline disorders
P5CS deficiency ( ALDH18A1 )	Infantile cutis laxa phenotype
	Microcephaly, progeroid features, mental retardation, hypotonia, seizures, movement disorders, joint laxicity, (intra uterine) growth retardation, cataract, corneal abnormalities	Decrease of proline, ornithine, citrulline and arginine can be found. Most patients no biochemical abnormalities Molecular testing preferred	L-ornithine therapy unsuccessful (2 sibs), L-arginine 150mg/kg/day (1 patient)	L-arginine resulted in progression of psychomotor development, correction of biochemical abnormalities and increase of brain creatine
	Skin: cutis laxa, wrinkly skin
	MRI: hypomyelination, thin corpus callosum, cerebellar abnormalities, tortuosity of brain vessels, low creatine peak on MRS
	Adult phenotype
	Spastic paraparesis, psychomotor delay, cognitive defects, cataract, cyclic vomiting	Low plasma citrulline in dominant form of spastic paraparesis, low value of the total sum of plasma citrulline, ornithine, proline and arginine in recessive form Molecular testing preferred	not reported
PYCR1 deficiency	Joint laxity, typical facial features, psychomotor retardation, osteopenia, intrauterine growth retardation, hypotonia, movement disorders. Similar symptoms as in P5CS deficiency, except for cataract and corneal abnormalities	No biochemical abnormalities Molecular testing	not reported
	Skin: cutis laxa, wrinkly skin
	MRI: thin or absent corpus callosum, white matter abnormalities
PYCR2 deficiency	Progressive microcephaly, severe failure to thrive, profound psychomotor retardation, typical facial features, seizures, spastic tetraplegia, ataxia, movement disorders	No biochemical abnormalities Molecular testing	not reported
	Skin: no abnormalities reported
	MRI: hypomyelination, thin corpus callosum, progressive cortical atrophy, cerebellar atrophy, thin brainstem, ventriculomegaly MRS elevated lactate
Asparagine deficiency	Progressive (congenital) microcephaly, intractable seizures, hypotonia, spastic quadriplegia, severe psychomotor retardation, hyperekplexia, diaphragmatic eventration	Inconsistent biochemical abnormalities, in some patients asparagine in plasma and CSF reported to be low Molecular testing	l-asparagine 20mg/kg/day	Worsening of seizures
	Skin: no abnormalities
	MRI hypomyelination, delayed myelination, cortical and cerebellar atrophy, decreased size of pons, ventriculomegaly, simplified gyration,

ADL activities of daily living, CSF cerebrospinal fluid, CNS central nervous system, EMG electromyography, IUGR intrauterine growth retardation, MRI magnetic resonance imaging, MRS magnetic resonance spectroscopy, ND not detectable, P5CS pyroline-5-carboxylate synthase, PYCR1 pyroline-5-carboxylate reductase 1, PYCR2 pyroline-5-carboxylate reductase 2