Serine Biosynthesis Deficiencies (PHGDH, PSAT1, PSPH) and Neu-Laxova Syndrome

Autosomal recessive inborn errors of the phosphorylated pathway of de novo L-serine synthesis, forming a continuous spectrum that extends from Neu-Laxova syndrome, lethal in the prenatal or neonatal period, to the infantile, juvenile, and adult forms, with targeted treatment by oral L-serine supplementation, sometimes combined with glycine, whose efficacy depends on the timing of initiation.

Literature and regulatory information updated: 17 October 2026.

0. Reference Summary Table

1. Introduction

1.1. Historical overview of Neu-Laxova syndrome

The history of this group of disorders has two origins that converged only in 2014. The first is dysmorphological. In 1971, Neu, Kajii, Gardner, and Nagyfy described in Pediatrics three siblings with intrauterine growth restriction and multiple congenital anomalies, including microcephaly and abnormalities of the limbs, skin, external genitalia, and placenta; two girls were stillborn and a boy died at 7 weeks [4, 30]. In 1972, Laxova, Ohara, and Timothy reported another sibship of three affected children born to first cousins and proposed a lethal autosomal recessive disorder [31, 32]. Lazjuk and colleagues coined the name "Neu-Laxova syndrome" in 1979 to bring these reports together [4, 33]. Clinical and pathological descriptions accumulated over the following decades: Scott and colleagues counted 13 cases in 1981 and defined a lethal dysplasia–malformation syndrome with abnormal placentation, severe intrauterine growth restriction, oedema, ectodermal dysplasia, and a severe developmental defect of the central nervous system; Shapiro and colleagues made a prenatal ultrasound diagnosis in 1992; and Manning and colleagues reviewed 61 cases in 2004, most of them sporadic but including at least 10 families with several affected children, of diverse ethnic origins, and concluded that the phenotype could be heterogeneous [4, 34].

1.2. Serine biosynthesis deficiencies as inborn errors of metabolism

The second origin is biochemical. In 1996, Jaeken and colleagues described two brothers of Turkish origin, born to first cousins, with congenital microcephaly, profound psychomotor delay, hypertonia, epilepsy, growth retardation, and hypogonadism; the younger had bilateral congenital cataracts, and magnetic resonance imaging (MRI) showed dysmyelination [1, 35]. Serine was markedly low in CSF and, to a lesser degree, in plasma, as was glycine; 3-phosphoglycerate dehydrogenase activity in fibroblasts was 22% and 13% of the control mean, and oral serine in the younger brother raised CSF serine and abolished the seizures [35]. The authors emphasised that this was the first inborn error of an amino acid synthesis pathway, in contrast to most aminoacidopathies, which are catabolic defects [1, 35]. In the same year, the group also described the first patient with deficiency of the last step of the pathway, 3-phosphoserine phosphatase [21, 36], reported in detail in 1997: a Belgian boy with prenatal and postnatal growth retardation, moderate psychomotor delay, and dysmorphic features suggestive of Williams syndrome, confirmed by a submicroscopic deletion at 7q11.23, with phosphoserine phosphatase activity of about 25% of normal in lymphoblasts and fibroblasts [11, 37].

1.3. Milestones of molecular discovery

In 2000, Klomp and colleagues characterised the PHGDH gene in six patients from four families: five patients from three families were homozygous for p.(Val490Met) and one for p.(Val425Met), both in the C-terminal regulatory domain, with significantly reduced activity on in vitro expression [1, 38]. In 2004, Veiga-da-Cunha and colleagues identified the two PSPH variants of the 1997 patient, p.(Asp32Asn) and p.(Met52Thr), and showed that the gene lies 16.5 million base pairs from the elastin gene, with no causal relationship to the concomitant Williams syndrome [11, 39]. In 2007, Hart and colleagues described phosphoserine aminotransferase deficiency in a British brother and sister, completing the identification of defects in all three steps of the pathway [40]. Méneret and colleagues described the first adult with 3-PGDH deficiency in 2012, a 31-year-old man with a Charcot-Marie-Tooth–like polyneuropathy [41]; Byers and colleagues reported the first adult with phosphoserine phosphatase deficiency in 2016 [13], and Debs and colleagues, in 2021, the first adult with phosphoserine aminotransferase deficiency to be diagnosed and treated [42].

The two lines of research converged in 2014. Using autozygosity mapping and exome sequencing in three consanguineous families from Saudi Arabia, Shaheen and colleagues identified biallelic PHGDH variants and proposed that Neu-Laxova syndrome is the severe end of an already known inborn error of serine metabolism [33]. In the same year, Acuna-Hidalgo and colleagues studied 12 families and found variants in PSAT1 in six, in PHGDH in three, and in PSPH in one, demonstrating that the syndrome is genetically heterogeneous and can result from defects in any of the three enzymes [9, 15].

1.4. Nomenclature and classification

Nomenclature varies by source. GeneReviews uses the collective term serine deficiency disorders and arranges them along a continuous phenotypic spectrum with four presentations: Neu-Laxova syndrome, infantile-onset form, juvenile-onset form, and adult-onset form; it establishes no gene–phenotype correlation, because each presentation occurs with any of the three genes [3]. OMIM keeps separate entries by gene and by severity: 601815 (PHGDH deficiency) and 256520 (Neu-Laxova 1) for PHGDH; 610992 (PSAT deficiency) and 616038 (Neu-Laxova 2) for PSAT1; and 614023 (PSP deficiency) for PSPH, with no entry of its own for PSPH-related Neu-Laxova syndrome, whose association is recorded as pending confirmation [1, 4, 6, 9, 11]. Orphanet uses a group (ORPHA:35705), an umbrella entity for the nonlethal forms (ORPHA:583595) with one subtype per gene, and three Neu-Laxova syndrome subtypes, one per gene [14, 16–18]. The mapping between OMIM and Orphanet is as follows: 601815 to ORPHA:79351, 256520 to ORPHA:583607, 610992 to ORPHA:284417, 616038 to ORPHA:583602, and 614023 to ORPHA:79350. The GeneGuidance database links 256520 to ORPHA:79351 and 616038 to ORPHA:284417, which swaps the lethal and nonlethal forms; Orphanet's own mapping prevails [2, 5, 43, 44]. The entity ORPHA:422519 ("3-phosphoglycerate dehydrogenase deficiency") is flagged as obsolete.

1.5. Definition of the entities in scope

Neu-Laxova syndrome is defined by the combination of severe growth restriction of prenatal onset, microcephaly, characteristic facial dysmorphism (sloping forehead, proptosis with absent or short eyelids, flattened nose, round open mouth with thick lips), thin, taut skin with collodion-type ichthyosis, oedema of the hands and feet, flexion contractures, and central nervous system malformations, with prenatal or neonatal death in most cases [3, 4, 32]. The infantile-onset form corresponds to congenital or early postnatal microcephaly, refractory epilepsy, severe developmental delay, spastic tetraplegia, and hypomyelination [3, 23]. The juvenile-onset form is characterised by absence seizures at school age, mild to moderate intellectual disability, and behavioural disorders, with normal MRI [3, 45]. The adult form presents as a progressive sensorimotor axonal polyneuropathy, sometimes with ataxia, congenital cataracts, ichthyosis, and mild cognitive impairment [3, 41, 42]. The diagnosis of any of these entities is established by identifying biallelic pathogenic or likely pathogenic variants in PHGDH, PSAT1, or PSPH in a patient with suggestive findings [3].

The scope excludes, as separate entities, deficiency of the neutral amino acid transporter ASCT1 encoded by SLC1A4, hereditary sensory and autonomic neuropathy type 1 (HSAN1) due to variants in SPTLC1 or SPTLC2, malate-aspartate shuttle defects (such as GOT2 deficiency) and asparagine synthetase deficiency; these conditions are treated as differential diagnoses in section 6.

2. Molecular Genetics and Pathophysiology

2.1. The phosphorylated pathway of L-serine synthesis

L-serine is classified as a nonessential amino acid because the body synthesises it from cellular precursors, but its functions have led to its being considered conditionally essential [3]. There are four sources of L-serine: dietary absorption, breakdown of proteins and phospholipids, synthesis from glycine by serine hydroxymethyltransferase, and de novo synthesis from the glycolytic intermediate 3-phosphoglycerate, which is the main source [3, 40]. De novo synthesis follows the phosphorylated pathway in three steps. D-3-phosphoglycerate dehydrogenase (PHGDH), the rate-limiting, nicotinamide adenine dinucleotide (NAD⁺)–dependent enzyme, oxidises 3-phosphoglycerate to 3-phosphohydroxypyruvate; phosphoserine aminotransferase (PSAT), a pyridoxal 5′-phosphate–dependent homodimer, transaminates this compound with L-glutamate, forming O-phosphoserine and 2-oxoglutarate; and phosphoserine phosphatase (PSP), which is magnesium dependent, removes the phosphate in an irreversible reaction to yield L-serine [8, 23, 43, 44]. Because PSP catalyses an irreversible reaction and there is no free serine kinase, the phosphorylated pathway serves only to produce serine; the so-called nonphosphorylated pathway, through D-glycerate and hydroxypyruvate, serves mainly for degradation [40]. PSP is inhibited by L-serine, so the pathway is regulated by demand [13].

The brain's dependence on this pathway stems from two facts. Serine crosses the blood–brain barrier poorly, and dietary intake is insufficient to meet the needs of the central nervous system, which relies on local synthesis [23, 40]. In the brain, synthesis is confined to astrocytes, and serine is transferred to neurons by a neutral amino acid transporter, ASCT1, encoded by SLC1A4 [23]. Work in mouse models has shown that ASCT1 is also an L-serine transporter at the blood–brain barrier [46].

2.2. Functions of serine and its derivatives

Serine is a precursor of glycine, D-serine, cysteine, phosphatidylserine, sphingomyelins, cerebrosides, and ceramides, and it is the main source of one-carbon units, in the form of N5,N10-methylenetetrahydrofolate, required for purine and thymidine synthesis and for methylation reactions [3, 21, 23]. Serine racemase converts L-serine into D-serine, a coagonist of the N-methyl-D-aspartate (NMDA)-type glutamate receptor; glycine is the other coagonist of this receptor [3, 21]. The interconversion of serine and glycine by serine hydroxymethyltransferase explains why, in synthesis defects, glycine is low or at the lower limit of normal [40].

2.3. Disease mechanism

The mechanism is loss of function [3]. Unlike the catabolic aminoacidopathies, in which damage arises from the accumulation of a metabolite, the key determinant here is the lack of the end product. Substrate accumulation is unlikely because 3-phosphoglycerate is a glycolytic intermediate, and the phenotypic similarity between severe PHGDH deficiency and ASCT1 transporter deficiency suggests that cerebral serine deficiency is the main determinant of disease [23, 40]. GeneReviews attributes the manifestations to four consequences [3]. Microcephaly and the neurodevelopmental manifestations of prenatal and infantile onset result from defective neuronal proliferation and migration. Hypomyelination and the skin changes result from insufficient phospholipid synthesis. Seizures relate to deficient NMDA receptor activation due to insufficient synthesis of D-serine and possibly glycine. The reduced pool of one-carbon units impairs nucleotide synthesis; by analogy with folate deficiency, Acuna-Hidalgo and colleagues proposed that the growth restriction and malformations of Neu-Laxova syndrome result from impaired proliferation, and they described the syndrome as a metabolic form of microcephalic primordial dwarfism [15]. 5-Methyltetrahydrofolate is markedly low in CSF, and the megaloblastic anaemia reported in two patients was associated with low CSF methyltetrahydrofolate: conversion of serine to glycine generates methylenetetrahydrofolate, which is then reduced to methyltetrahydrofolate [3, 23, 47]. D-serine is decreased in CSF in 3-PGDH deficiency [40].

Metabolomics has added data on the lipid compartment. In four children (three with PHGDH deficiency and one with PSAT deficiency), Glinton and colleagues found low glycerophosphocholine in 4/4, low glycerophosphoethanolamine in 3/4, and low sphingomyelin in 2/4; serine and glycine supplementation normalised most of the low phospholipids, and the authors proposed that secondary phosphatidylcholine deficiency contributes to the neurological manifestations [48]. Ferreira and colleagues showed a statistically significant elevation of 18- to 22-carbon deoxydihydroceramides in patients with primary serine deficiency: when serine is lacking, serine palmitoyltransferase uses alanine or glycine and forms neurotoxic 1-deoxysphingolipids, in a pattern similar to that of mitochondrial diseases with low serine, high alanine, and peripheral neuropathy [49]. This mechanism is the leading hypothesis for the axonal neuropathy of the adult forms, by analogy with HSAN1, and the lack of physiological sphingolipids and phospholipids is another hypothesis [8]. For the ichthyosis, Shen and colleagues listed three hypotheses: the role of serine in the active site of the serine proteases that cleave profilaggrin into filaggrin, deficiency of stratum corneum sphingolipids, and deficiency of activated tetrahydrofolate affecting epidermal cell division [8].

Treatment with L-serine restores the metabolites and normalises serine, glycine, 5-methyltetrahydrofolate, and D-serine; brain phospholipids are not quantified directly, but white matter expands significantly after treatment, which is interpreted as recovery of phospholipid synthesis [3, 50].

2.4. Genes, proteins, and identifiers

2.5. Inheritance

All forms are autosomal recessive [3, 21]. Sibships with several affected members and parental consanguinity are common in published cohorts, particularly in Neu-Laxova syndrome: among the 12 families of Acuna-Hidalgo and colleagues, there was consanguinity in nine and distant relatedness, revealed by array, in one more [15]. Absence of a family history does not exclude the diagnosis [3]. One family has been described in which three fetuses of Chinese parents with no known consanguinity were homozygous for a PHGDH start-loss variant, within an 11.2-Mb region of homozygosity indicating a distant common ancestor [4].

2.6. Variant spectrum and normalisation

The PHGDH, PSAT1, and PSPH literature uses numbering from the A of the initiation codon, matching the current MANE transcripts, so no conversion of historical numbering was needed; the old abbreviated protein designations ("V490M," "c.delG107") were normalised in VariantValidator, on GRCh38 [19]. In 2022, SAUD listed 27 variants in PHGDH and eight in PSAT1 [23]. In PHGDH, variants are distributed throughout the gene [21]; in 2009, Tabatabaie and colleagues showed that missense variants in the nucleotide-binding and regulatory domains do not affect protein expression or stability but significantly and incompletely reduce maximal activity in fibroblasts; p.(Arg135Trp) and p.(Val261Met) lower the maximal velocity (Vmax) and raise the Michaelis constant (Km), altering substrate and cofactor binding [51]. For p.(Val490Met), Klomp and colleagues measured a Vmax of 41% of wild type (58% for p.(Val425Met)), whereas Pind and colleagues attributed the effect to a folding and assembly defect with increased degradation, resulting in a lower yield of mature enzyme [38, 52].

Some variants from the literature are not normalised here for lack of the original source: the variants of Méneret's patient, for which Shen and colleagues give inconsistent notation; and p.(Gly429Val) in a boy from the United Arab Emirates and p.(Arg163Trp), recorded by OMIM in protein notation only [1, 8]. In PSPH, the variant c.662G>A p.(Gly221Glu) was not considered causal because of lack of cosegregation [15].

2.7. Founder variants and populations

Recurrent variants are associated with specific populations. PHGDH p.(Val490Met) was found in the homozygous state in two families from the Konya region of Turkey with no known relationship and in two European sisters with a different haplotype, which, together with its location in a CpG dinucleotide, indicates recurrent origin [38]; Pind and colleagues found it in an Ashkenazi Jewish family and identified one heterozygote among 400 Ashkenazi individuals, with none among 400 non-Jewish controls [52]. PHGDH p.(Gly140Arg) shares a haplotype in two Saudi families [33]. PSAT1 c.296C>T p.(Ala99Val) shares a haplotype in families from Turkey and Iran [15], and PSAT1 c.734G>A was proposed as a founder variant in Egypt in a cohort of 12 families [58]. PSPH c.103G>A p.(Ala35Thr) was described in a Pakistani family [59].

2.8. Genotype–phenotype correlations and residual activity

There is no correlation between gene and phenotype: each presentation occurs with any of the three genes [3]. For PHGDH and PSAT1, there are preliminary conclusions regarding the affected domain. Neu-Laxova syndrome is predominantly associated with variants in the substrate-binding and nucleotide-binding domains (83%), and substrate-binding domain variants have not been described in the infantile, juvenile, or adult forms; in the nonlethal forms, variants lie mainly in the regulatory domain (63%) [3, 60]. Nonsense variants are rare, even in Neu-Laxova syndrome, and the GeneReviews authors are not aware of any patient with two nonsense variants, which may reflect early lethality [3]. In 15 families with severe forms, Abdelfattah and colleagues described a continuous spectrum and postulated residual activity as the main determinant of variability [60]; Mattos and colleagues interpreted homozygous p.(Gln433Ter) as supporting a correlation between the degree of inactivation and severity [56].

Residual activity measured in fibroblasts does not predict the phenotype. In the nonlethal forms, reported PHGDH residual activities are 6–22% according to SAUD and 12–25% of the lower limit of the reference range according to the Atlas of Inherited Metabolic Diseases, two expressions that use different denominators [15, 21, 23]. In the Dutch siblings with the juvenile form, activity was 6.8 and 3.1 nmol/min/mg protein (reference 33.1 ± 1.9), the same as in the infantile forms (3.1–7.3), and CSF and plasma serine were identical to those of the infantile form [45]. Shen and colleagues relate severity to residual enzyme activity rather than to plasma serine [8]. The absence of biallelic complete null alleles in PSAT1 and PHGDH suggests that some residual activity is required for viability; the presence of a probable homozygous PSPH null allele in Neu-Laxova syndrome suggests that the final step can be partially bypassed by nonspecific phosphohydrolases [15]. In the PSAT-deficient siblings of Hart and colleagues, the combination of a null allele with a severe missense variant reduced fibroblast activity by only about 50% [40].

2.9. Allelic disorders and heterozygosity

GeneReviews recognises no phenotypes associated with germline variants in PHGDH, PSAT1, or PSPH other than the serine deficiency spectrum [3]. Subsequent data give clinical relevance to PHGDH heterozygosity. In a dominant collapsed rare-variant analysis of 793 patients with macular telangiectasia type 2 (MacTel) and 17,610 controls, PHGDH reached genome-wide significance (P = 1.2 × 10⁻¹³), and the variants accounted for about 3.2% of cases; the functional defects reduced serine synthesis and led to deoxysphingolipid accumulation in retinal pigment epithelial cells [61]. A Mendelian randomisation study identified genetically determined serine deficiency as the main causal metabolic factor in the occurrence and progression of MacTel [62]. Gantner and colleagues measured 84.2% higher circulating deoxysphingolipids and 20.6% lower serine in 125 patients with MacTel without serine palmitoyltransferase variants compared with 94 controls, and found MacTel in 9 of 11 patients with HSAN1 [63]. In the Phgdh+/− mouse, dietary serine and glycine restriction accelerated retinal defects, and serine-associated retinopathy and neuropathy reversed with supplementation (preclinical data) [64]. These data make PHGDH heterozygosity a low-penetrance risk factor for late-onset retinal disease, but not a Mendelian allelic disorder.

2.10. Animal models

The Phgdh−/− mouse dies at around embryonic day 13.5, with oedematous, undigitated limb buds, deficiency of brain sphingolipids and gangliosides, and impaired neural progenitor proliferation, recapitulating features of Neu-Laxova syndrome; heterozygotes are normal [33]. Psat1 knockout is associated with severe craniofacial and brain malformations [15]. Variant effect maps of PSAT1 in yeast assessed 199 missense variants by complementation and then 1914 substitutions accessible by a single nucleotide substitution; the ranges defined may help interpret up to 98% of the variants tested, and a diploid assay distinguished affected from carrier genotypes, in agreement with severity [65, 66].

3. Clinical Spectrum and Manifestations by System

3.1. Overview of the spectrum

GeneReviews describes a continuous spectrum with four presentations, all possible with any of the three genes [3]. Most of the more than 50 individuals with a molecular diagnosis have the infantile-onset form [3]. In SAUD, the 53 known patients with PHGDH deficiency (38 families, including unpublished cases) were distributed across four presentations, with a predominance of the severe infantile phenotype [23]. The comparison below summarises the essential differences and, where the data allow, separates untreated from treated disease.

The GeneReviews frequencies for the infantile form (68%, 95%, 63%, 42%, 16%) come from the published series of more than 50 patients, without a per-item denominator, and the SMITH frequencies for Neu-Laxova syndrome come from a compilation of literature cases, also without a denominator [3, 32].

3.2. Neu-Laxova syndrome

Neu-Laxova syndrome is the most severe end of the spectrum and can result from a defect in any of the three steps of biosynthesis [21, 23]. Growth restriction becomes evident in the second trimester; a head circumference of 20 cm at term has been described, and Lazjuk recorded a brain weight of 19.8 g in a 39-week fetus [4, 33]. The face shows a sloping forehead, marked proptosis with ectropion, hypertelorism, absent or short eyelids, a flattened nose, a round open mouth with thick everted lips, micrognathia, large, low-set, or malformed ears, and a short neck [3, 4, 32]. The skin is thin, transparent, and taut, with collodion-type ichthyosis or scaling, overlying yellow subcutaneous tissue with adipose tissue hypertrophy and atrophic muscles embedded in it; in 1982, Curry proposed two groups, with and without oedema and an enlarged fat layer [4, 32]. The limbs are short, with cutaneous syndactyly, overlapping fingers, extreme oedema of the hands and feet, rocker-bottom feet, flexion contractures of the large joints with pterygia, and poorly mineralised bones [3, 32]. The central nervous system shows microcephaly, lissencephaly (described as "type III" by Shaheen and colleagues), agenesis or hypoplasia of the corpus callosum, hypoplasia of the cerebellum, pons, and vermis, small corticospinal tracts, absent olfactory bulbs, and neural tube defects; MRI shows cortical dysplasia with anterior-predominant gyral simplification, enlarged ventricles, and reduced white matter [3, 32, 33].

The molecular series added further detail. In family 1 of Shaheen and colleagues, whose parents were double first cousins, the newborn died shortly after delivery, with absent eyelids, severe ichthyosis, cleft lip and palate, and indistinguishable digits; in family 2, ultrasounds at 19 and 24 weeks showed polyhydramnios, a curved spine, prominent eyes, an open mouth, skin oedema, flexed hands, rocker-bottom feet, and fetal akinesia, with delivery at 29 weeks; in family 3, the term newborn weighed 2.24 kg, had a head circumference of 27.5 cm and collodion-type ichthyosis, and died at 1 month of pneumonia and Pseudomonas sepsis [33]. In the six families with PSAT1 variants reported by Acuna-Hidalgo and colleagues, two patients were liveborn and died within the first 2 weeks; the rest were stillborn [9]. One family in the same cohort had an atypical picture, without oedema, with mild ichthyosis, longer postnatal survival, dysplastic kidneys, and pancreatic insufficiency [15]. The Egyptian cohort of 12 families (fetal phenotyping and exome) described new manifestations: intrauterine seizures, hemivertebrae, natal teeth, holoprosencephaly, and rhombencephalosynapsis [58]. Bourque and colleagues described three fetuses with increased nuchal translucency or cystic hygroma in the first trimester, growth restriction, microcephaly, micrognathia, arthrogryposis, and oedema, without proptosis or ichthyosis, possibly because of the early gestational age, and with congenital agenesis of the corticospinal tracts and hypoplasia of the hippocampus, cerebellum, and brainstem; the family also had five unstudied first-trimester losses [4].

Survival differs between sources. SMITH states that most are stillborn or die in the immediate neonatal period, with survival beyond 10 months reported, and that death is usually due to respiratory failure or to sepsis secondary to the skin lesions [32]. GeneReviews reports survival up to 2 months, based on the series of Shaheen (2014) and El-Hattab (2016) [3, 67]. Shaheen and colleagues cite a 10-month-old infant with a mild form of Neu-Laxova as an argument for a continuous spectrum, which is consistent with the SMITH figure; the two sources therefore describe different points on the spectrum and are not mutually exclusive [33].

3.3. Infantile-onset form

The untreated infantile form manifests from birth with feeding difficulties with vomiting and irritability with inconsolable crying [21, 23]. Microcephaly is congenital in 68% and postnatal in 95% of patients [3]. Seizures begin in the first weeks or months and are refractory to antiseizure medications in almost all patients; some have 60–70 clinically evident tonic-clonic seizures per day [3, 23]. About one third have infantile spasms with hypsarrhythmia on the electroencephalogram (EEG), with arrest of head growth; the rest have myoclonic, tonic-clonic, gelastic, tonic, or atonic seizures, sometimes evolving into Lennox-Gastaut syndrome [3, 68]. Hypertonia in the first year progresses to spastic tetraplegia (63%) [3, 23]. Psychomotor development is very poor: in patients described up to age 24, developmental age was less than 1 year [23]. Other manifestations are intrauterine growth restriction (16%), postnatal growth failure (42%), feeding difficulties (37%), nystagmus (42%), and congenital cataracts (26%), which are bilateral and recognised in the first months [3]. In a limited number of patients, across all phenotypes, adducted thumbs, inguinal and umbilical hernias, hypogonadism, abnormal hair, megaloblastic anaemia, and generalised ichthyosis have been reported [3, 21]. In unpublished data, the GeneReviews authors describe a long face, large ears, upslanting palpebral fissures, and a broad nasal tip, more apparent in older patients [3]. MRI shows cortical and subcortical hypotrophy, delayed myelination, severe hypomyelination with white matter attenuation, and nonspecific cerebellar changes [3, 23, 50].

Variability within the infantile form is wide. In family 3 of Benke and colleagues, three sisters born to consanguineous Arab parents had microcephaly (and, in two, cataracts) at birth; one walked at 2.5 years and lost ambulation because of spasticity at 5 years, another had normal development through the first year, seizures at 4 years, and regression at 8 years, and the eldest had seizures at 6 months and stopped walking at 12 years [1]. In Chinese siblings homozygous for p.(Val404Asp), pregnancy, the perinatal period, and early development were normal, with microcephaly and seizures at 4 years and later cognitive impairment [1, 57]. In the infantile form due to PSAT deficiency, microcephaly was acquired in the siblings of Hart and colleagues, unlike most patients with 3-PGDH deficiency, in whom it is congenital [40]. Shapira Zaltsberg and colleagues described a patient with PSAT deficiency with microencephaly and anterior-predominant gyral simplification already visible on fetal MRI at 35 weeks [69].

3.4. Juvenile-onset form

The juvenile form was defined by Tabatabaie and colleagues in two Dutch siblings, born to nonconsanguineous parents, homozygous for PHGDH c.1129G>A p.(Gly377Ser) [45]. The boy was born with weight, length, and head circumference at the 3rd percentile, had slow milestone acquisition, absence seizures at 9 years with 3-Hz spike-and-wave complexes on EEG, and an IQ of 49 at 16 years, with head circumference at the 10th percentile, joint hyperlaxity, striae, and normal MRI. His sister was normal at birth, had delay after age 4, absences at 5, an IQ of 55, and severe obesity [45]. Neither was microcephalic [21]. GeneReviews generalises: seizures at school age, with absences between 4 and 9 years in one cohort, drug resistant in one individual; EEG with bilateral synchronous 3-Hz spike-and-wave complexes, accentuated by hyperventilation; normal or mildly delayed motor and language development; normal cognition or mild impairment; hyperactivity, behavioural problems, and mood changes, although normal behaviour has also been described; and progression to spastic tetraparesis and spinal and limb deformities in many [3, 8, 45].

3.5. Adult form and neuropathy-predominant forms

The neuropathy-predominant phenotype, resembling Charcot-Marie-Tooth disease type 2 (CMT2), had been described in five patients by 2022 (three with PSAT1, one with PHGDH, one with PSPH): all had neuropathy, four had multidirectional nystagmus, three intellectual disability, and two intrauterine growth restriction; all survived into adulthood and improved with treatment [8]. Ichthyosis in adults occurred only in the PSAT1 cases [8].

The neuropathy is axonal, sensorimotor, and severe, with a possible demyelinating component; sural nerve biopsy showed severe loss of myelinated and unmyelinated fibres, and skin biopsy showed orthokeratotic hyperkeratosis with loss of the granular layer and loss of unmyelinated axons [8, 42]. Plasma serine may be at the lower limit of normal, as in patient 1 of Shen and colleagues, particularly in nonfasting samples [8]. Méneret and colleagues recommended plasma amino acid chromatography in the workup of Charcot-Marie-Tooth–like polyneuropathies, especially with psychomotor delay and congenital cataracts [41].

3.6. Gene-specific features

PHGDH deficiency is the most common (69% of patients) and spans the entire spectrum [3, 23]. For PSAT deficiency, Shen and colleagues reviewed 31 patients (29 from the literature and 2 new): 13 male, 15 female, and 1 of undetermined sex; 14 from consanguineous families; 18 died at birth or in the first month; and onset ranged from the intrauterine period to 4 years. Microcephaly was present in 24/26 (92.3%), intrauterine growth restriction in 11/15 (73.3%), ichthyosis in 21/24 (87.5%), and epilepsy in 2/10 (20.0%) [8]. At the time, SAUD listed six patients with PSAT deficiency from five families, excluding Neu-Laxova syndrome [23]. For PSP deficiency, SAUD listed nine patients from three families, including one adult and one family with seven affected siblings, with intellectual disability, epilepsy, microcephaly, and growth failure [23]. The consanguineous Pakistani family of Vincent and colleagues had seven affected members aged 5 to 19 years, all with severe delay in infancy and childhood, moderate to profound intellectual disability, seizures, and hypertonia, and microcephaly in most; serine was 26–29 µmol/L (reference 75–175) and glycine 102–129 µmol/L (148–324) [11, 13, 59]. The 1997 index patient had a CSF serine of 18 µmol/L (controls 27–57) and plasma serine of 53–80 µmol/L (normal 70–187), normalising after meals, and started serine at 1 year, with some head growth and progress, before being lost to follow-up after age 2 [13, 37].

3.7. Manifestations by system

In the central nervous system, microcephaly, epilepsy, spasticity, and intellectual disability predominate; SAUD lists serine synthesis defects among the metabolic causes of congenital and postnatal microcephaly improved by serine, of hypomyelination, of gyration and corpus callosum anomalies, of a cerebral palsy–like picture, and of treatable ataxia [70]. In the eye, bilateral congenital cataracts and nystagmus are the characteristic findings; macular lesions and mild optic atrophy have been described in the adult PSAT1 forms [3, 8, 42]. In the skin, ichthyosis ranges from the collodion type of Neu-Laxova syndrome to the fine scaling, worse in winter, of the juvenile and adult forms, and is sometimes accompanied by hair changes (trichoschisis, trichorrhexis nodosa, alopecia) and nail changes [3, 8, 42]; SAUD lists the combination of ichthyosis and optic atrophy as a sign of serine deficiency syndrome [70]. In the peripheral nervous system, axonal polyneuropathy is the hallmark of the adult forms [3]. Regarding hearing, severe to profound bilateral sensorineural hearing loss has been described in an adult with PSAT1 deficiency who received a cochlear implant, as has low-frequency hearing loss with semicircular canal dysfunction in an adolescent [8, 42]. In the endocrine and reproductive systems, hypogonadism has been described in the infantile form and primary ovarian insufficiency at age 39 in one adult, without serine deficiency having been excluded as the cause [3, 42]. In the musculoskeletal system, contractures, kyphoscoliosis, and foot deformities result from spasticity and neuropathy; one adult had osteoporosis with a femoral T-score of −3.6 [3, 42]. In the blood, megaloblastic anaemia is rare and is associated with low 5-methyltetrahydrofolate [23].

3.8. Natural history and treated disease

The natural history of the infantile form as known until the end of the 1990s is that of patients diagnosed late: development plateaus in the first year, with a developmental age of about 1 year, and diagnosis after the first months, and especially after 6 months, is associated with severe delay [3]. With treatment, the picture changes along two distinct dimensions. Seizures, irritability, and feeding improve in all treated patients, at any age, but development is normal only in patients treated prenatally or immediately after birth; those treated from 4 months of age or later remain severely delayed and function at a preschool level in adulthood [3, 40, 71]. In the adult form, supplementation stabilised the neuropathy and resolved the skin lesions, without recovery of established neuropathy [8, 42]. Data on treated disease come from case series and isolated reports, without controlled studies (section 7).

4. Clinical Recognition and Red Flags

4.1. When to suspect, by age

In the prenatal period, suspicion arises with severe, early fetal growth restriction with microcephaly, especially when accompanied by proptosis, an open mouth, oedema of the skin and of the hands and feet, flexion contractures, rocker-bottom feet, polyhydramnios, or fetal akinesia [4, 33]. Manning and colleagues considered that marked proptosis in a fetus with growth restriction and oedema should prompt consideration of Neu-Laxova syndrome [4]. Increased nuchal translucency and cystic hygroma in the first trimester were the first manifestations in fetuses with PHGDH variants, and the syndrome is a possible cause of recurrent increased nuchal translucency [4, 55]. In an at-risk pregnancy, deceleration of fetal head circumference growth, from the 75th percentile at 20 weeks to the 29th percentile at 26 weeks, was the sign that prompted maternal treatment [71]. In the setting of fetal akinesia, yellow subcutaneous tissue covered by thin, scaling skin and generalised oedema point towards Neu-Laxova [72].

In the newborn and infant, the red flags are congenital microcephaly, congenital cataracts, feeding difficulties with vomiting, irritability with inconsolable crying, and seizures beginning in the first weeks that are refractory to antiseizure medications, including infantile spasms [3, 23]. SAUD includes low plasma and CSF serine among the markers of neonatal seizures of metabolic cause and places defects of serine, asparagine, and glutamine synthesis in the group of neonatal neurological deterioration without a first-line metabolic disturbance, whose diagnosis requires plasma and CSF amino acids [70]. The Oxford Desk Reference lists 3-PGDH deficiency among the causes of neonatal encephalopathy and intractable seizures, with microcephaly and psychomotor delay as supporting signs [73]. Microcephaly may be acquired, as in the PSAT-deficient siblings of Hart and colleagues, whose head circumference was at the 9th percentile at birth [40].

In the school-age child, suspicion arises with absence seizures accompanied by mild intellectual disability, behavioural disorders, and normal MRI [3, 45]. In adolescents and adults, suspicion arises with progressive axonal polyneuropathy resembling Charcot-Marie-Tooth disease type 2, especially when there is psychomotor delay, intellectual disability, congenital cataracts, ichthyosis, nystagmus, hearing loss, contractures, or nonhealing ulcers [8, 13, 41, 42]. Byers and colleagues recommended fasting plasma amino acids in adults with unexplained neuropathy and complex features [13]. The combination of ichthyosis with a neurological deficit mandates considering serine synthesis defects among the treatable neuroichthyotic syndromes [42, 70].

4.2. Clues that strengthen suspicion

Suspicion is strengthened by parental consanguinity, affected siblings, previous fetal losses (the mother of the patient of Debs and colleagues had had two first-trimester miscarriages and a stillbirth), and origin from populations with founder variants [3, 15, 42]. The infantile-onset form is distinguished from ASCT1 transporter deficiency by the microcephaly, which in the latter is progressive and postnatal, with normal head circumference at birth [70, 74].

4.3. Emergency signs

Status epilepticus and multiple daily seizures in an infant are emergencies; they require intensive care and frequently do not respond to antiseizure medications; in the index patient with PSAT deficiency, intractable seizures at 9 weeks required ventilation and thiopental [3, 40]. The urgency is also diagnostic: because neurodevelopmental outcome depends on early initiation of L-serine, fasting plasma and CSF amino acids and molecular testing should be obtained without delay in an infant with congenital microcephaly and seizures of unknown cause [3, 38]. In a newborn with an affected sibling, treatment should begin within the first hours or days, because serine is already low at 2 hours of life [40]. Keularts and colleagues described two girls with fatal acute toxic encephalopathy with cerebral oedema and markedly low plasma and CSF serine, without 3-PGDH deficiency; low serine in a severe acute illness may be secondary and should not delay investigation of other causes [75].

4.4. Newborn screening

No newborn screening programme described in the sources consulted includes serine biosynthesis deficiencies. The available data are isolated. In a Saudi family with Neu-Laxova, dried blood spot analysis by tandem mass spectrometry showed serine of 50 nmol/mL (reference 74–448) and glycine of 105 nmol/mL (reference 180–709) [33]. In a female infant with PSAT deficiency, retrospective analysis of the newborn screening blood spot showed low serine, with a Z-score of −2.4 [6]. These values do not validate serine as a screening marker: plasma serine depends on fasting status and age, and neonatal reference ranges are higher [3, 45].

5. Diagnosis: Criteria, Testing, and Algorithms

5.1. Criteria

No published consensus clinical diagnostic criteria exist [3]. GeneReviews defines suggestive clinical, biochemical, and imaging findings for each of the four presentations (sections 3 and 4) and establishes the diagnosis in a proband with these findings and biallelic pathogenic or likely pathogenic variants in PHGDH, PSAT1, or PSPH [3]. Biallelic variants of uncertain significance (VUS), or one pathogenic variant with a VUS, neither establish nor exclude the diagnosis [3].

5.2. Plasma and CSF amino acids

The laboratory finding consistent across all phenotypes is markedly low CSF serine, usually below 13 µmol/L and, in most cases, below 10 µmol/L; CSF serine in the infantile form does not differ significantly from that in the juvenile and adult forms [3, 68]. In 3-PGDH deficiency, the Atlas gives a CSF serine that is always ≤13 µmol/L, with a value of 13 µmol/L in the adult phenotype and 6–11 µmol/L in the others; in PSAT deficiency, 5–18 µmol/L; and in the patient with PSP deficiency, 18 µmol/L [21]. SAUD gives, in PHGDH deficiency, CSF serine of 6–8 µmol/L (controls 35–80 µmol/L) and plasma serine of 28–64 µmol/L (normal range 70–187 µmol/L), reference ranges without age specification [23]. Glycine is low to normal in CSF and in fasting plasma [3]. CSF 5-methyltetrahydrofolate is markedly low [3, 47]. Urinary amino acids are not informative and are usually normal [1, 3]. SAUD summarises the pattern: low serine with normal or low plasma glycine and low CSF glycine indicates serine deficiency; low plasma and CSF serine with increased citrulline suggests, alternatively, a malate-aspartate shuttle defect [76].

5.3. Preanalytical considerations: fasting and age

Plasma serine and glycine may be normal after a meal, so plasma amino acids should be collected in the fasting state [3, 23]. Unpublished data from Tabatabaie and colleagues show that, after a single oral load of 100 mg/kg of serine or glycine, the plasma peak occurs at 1–2 hours and the value returns to normal 4 hours later; the authors recommend sampling after an overnight fast or at least 4–6 hours after a meal [45]. In CSF, a single oral load has little effect, and serine rises only after weeks or months of treatment; CSF is therefore the preferred procedure for confirming the deficiency and is considered by the Atlas the diagnostic gold standard [21, 45]. In PSAT deficiency, the index patient's plasma serine was only marginally below the lower limit, and Hart and colleagues emphasised the need to measure CSF serine and glycine [40].

Reference ranges are age dependent, with higher serine values in the neonatal period, significantly higher between birth and 3 months [3, 21]. Moat and colleagues established multicentre reference ranges for CSF serine (9 laboratories, 424 samples, age regression); the 11 patients with synthesis defects (1 day to 13 years; CSF serine 5–18 µmol/L) were all identified with these ranges, whereas a single non–age-adjusted range (12.6–69.4 µmol/L) would have missed two cases [22].

Brassier and colleagues confirmed redefined ranges with more samples and recommended measuring CSF and plasma serine in all cases of severe microcephaly at birth [77]. Some centres have reference ranges for umbilical cord blood amino acids, usable together with fasting plasma serine in the at-risk newborn [3].

5.4. Enzyme assays

Deficient PHGDH activity in fibroblasts confirmed the diagnosis before the molecular era, with residual activities of 6–22% (SAUD) or 12–25% of the lower limit of the reference values (Atlas) [21, 23]. In PSAT deficiency, the fibroblast assay was inconclusive, with a reduction of only about 50% (0.9 versus 2.0 ± 0.3 nmol/min/mg protein, n = 9 controls), and the diagnosis was molecular; in PSP deficiency, the assay was definitive [21, 40]. Enzymology does not distinguish mild from severe forms [45]. When molecular testing yields a VUS, low PHGDH, PSAT, or PSP activity allows the diagnosis to be established, but because of the limited availability of substrates, these assays are no longer routinely available [3].

5.5. Molecular testing

GeneReviews proposes two approaches [3]. When the phenotype is distinctive, as with Neu-Laxova syndrome in the prenatal period, a multigene intellectual disability or epilepsy panel that includes the three genes may be used; when the phenotype is indistinguishable from other disorders with seizures and delay, exome sequencing is the most commonly used option, and genome sequencing an alternative [3]. Panel composition and sensitivity vary by laboratory [3]. Brassier and colleagues identified the variants with a three-gene panel, and Byers and colleagues sequenced PHGDH, PSAT1, and PSPH sequentially [1, 13].

The last two columns are proportions of known variants by method, taken from the HGMD database (Human Gene Mutation Database), and not the clinical sensitivity of the test [3].

5.6. Test limitations

A negative molecular result does not exclude the diagnosis. Sequencing may fail to detect deletions of one or more exons, which have been described in PHGDH (an intragenic deletion of at least three exons in trans with p.(Arg54Cys) in a family with Neu-Laxova) [3, 15]. Apparent homozygosity may correspond to a deletion on the other allele or to uniparental isodisomy [3]. Complex variants may not be called by standard bioinformatic analysis: PSAT1 c.1023_1027delinsAGACCT was not identified in the initial exome analysis [15]. Two of the 12 Neu-Laxova families of Acuna-Hidalgo and colleagues showed no linkage to any of the three genes, leaving open the possibility of additional heterogeneity [15]. The GeneReviews authors invite clinicians with families in whom no causal variant has been identified to contact them [3]. Biochemistry also has limitations: plasma serine may be normal in the nonfasting state or at the lower limit of normal, and low serine is not pathognomonic, because it occurs in secondary deficiencies (section 6) [8, 42, 75].

5.7. Report content and interpretation

The molecular report should state the gene, the versioned reference transcript (NM_006623.4, NM_058179.4, or NM_004577.4), the variant in HGVS nomenclature at the complementary DNA and protein levels, the zygosity, the phase when determined, and the classification according to the criteria of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) [3, 19]. Parental testing confirms phase and is recommended [3]. For VUS, family segregation, CSF biochemistry, and, when available, enzymology help with reclassification; yeast PSAT1 variant effect maps have been proposed as ACMG functional evidence [65, 66]. Shen and colleagues classified PSAT1 c.43G>C as pathogenic using criteria PS1, PS3, PM5, and PP1, supported by a yeast assay and by the pathogenicity of another variant at the same codon [8]. The GeneReviews authors offer to review VUS in PHGDH, PSAT1, and PSPH [3].

5.8. Practical algorithm

The algorithm organises the recommendations of GeneReviews and the cited series; it does not correspond to an algorithm published by a scientific society [3].

5.9. Prenatal and preimplantation diagnosis

Prenatal diagnosis is possible only by molecular analysis, because there are no data on enzyme activity in chorionic villi and amniocytes [23]. When the familial variants are known, it is performed by chorionic villus sampling or amniocentesis, and preimplantation genetic testing is also possible [3]. Brassier and colleagues measured reduced serine in fetal cord blood at 30 weeks in a pregnancy with severe fetal microcephaly in the family of a patient with PSAT deficiency, showing that fetal biochemical diagnosis is possible, albeit by an invasive procedure [77]. Without a prior molecular diagnosis, ultrasound suspicion of Neu-Laxova or severe, early fetal growth restriction may lead to fetal exome sequencing: in a dichorionic twin pregnancy conceived by in vitro fertilisation, Luo and colleagues observed increased nuchal translucency at 13+1 weeks, normal karyotype, fluorescence in situ hybridisation, and single nucleotide polymorphism array, severe growth restriction from 22 weeks, and a normal echocardiogram at 26+1; trio exome sequencing at 29+4 weeks identified paternal PHGDH c.488G>A p.(Arg163Gln) and a novel maternal c.1129G>C p.(Gly377Arg), and fetal MRI at 36+6 weeks showed agenesis of the corpus callosum, microcephaly, and micrognathia [55]. The authors recommend trio exome sequencing after a normal array in severe, early fetal growth restriction [55]. The Egyptian cohort used fetal phenotyping and exome sequencing in 12 families [58], and Serrano Olave and colleagues, in Spain, diagnosed the syndrome on second-trimester ultrasound, with confirmation in amniotic fluid of a homozygous PSAT1 variant; in the next pregnancy, the fetus was heterozygous [20].

6. Differential Diagnosis

6.1. Comparison table

6.2. ASCT1 transporter deficiency (SLC1A4)

The closest differential of the infantile form is ASCT1 transporter deficiency, whose phenotype closely resembles severe PHGDH deficiency [3, 23]. SAUD listed 19 patients in 2022 (in one passage of chapter 24 the gene is misspelled as "SLC4A1"; the chapter's own introduction, the cited references, and Orphanet give SLC1A4) [23, 82]. The triad is spastic tetraplegia, thin corpus callosum, and progressive postnatal microcephaly: head circumference is normal at birth and then falls, with severe global delay, severe intellectual disability, and, in most, absence of walking and speech; seizures are common and often refractory, including infantile spasms, and some patients have hypomyelination [74, 78, 79]. Biochemistry distinguishes the two conditions: in ASCT1 deficiency there are no associated biochemical abnormalities and plasma amino acids are not diagnostic, whereas in the synthesis defects CSF serine is low [3, 74]. The c.766G>A p.(Glu256Lys) variant is a founder variant in the Ashkenazi Jewish population, with a carrier frequency of about 1 in 100 according to Heimer and colleagues and 0.7% according to Damseh and colleagues, and an allele frequency of 0.0056 in 450 Ashkenazi controls according to Srour and colleagues; Damseh proposed its inclusion in the Ashkenazi carrier panel [78–80]. An 8-year-old boy has been described with a heterozygous de novo duplication, p.(Leu86_Met88dup), with a dominant-negative effect, global delay, spasticity, epilepsy, and microcephaly [81]. In three mouse models (constitutive knockout, residue 256 knock-in, and endothelial knockout), ASCT1 deficiency reduced serine influx into the brain and caused microcephaly, increased 1-deoxysphingolipids, and neurodegeneration, and prenatal and early postnatal L-serine corrected these changes, normalising brain weight when given up to the second postnatal week [46]. These data are preclinical; treatment of ASCT1 deficiency in humans remains supportive [74].

6.3. Secondary serine deficiencies

Low plasma and CSF serine is not exclusive to the primary deficiencies. Because the first step of synthesis is an NAD⁺-dependent oxidation-reduction reaction, defects that alter the cytosolic redox state can reduce serine synthesis [3]. In GOT2 deficiency, serine biosynthesis is impaired by an oxidised cytosolic NAD state, corrected by pyruvate in vitro; patients have low plasma serine, hypercitrullinaemia, hyperlactataemia, and hyperammonaemia, and the epilepsy responded to serine and pyridoxine, with complete seizure control in two of four patients [83, 84]. In its differential diagnosis section, GeneReviews mentions "GOT1 deficiency" as an example of a redox defect, but its table and the cited literature deal with GOT2 deficiency, which is the documented differential [3, 83]. SAUD adds neonatal hyperammonaemia with ketosis and high citrulline as the biochemical context of GOT2 deficiency [70]. In mitochondrial complex I deficiencies, the GeneReviews authors observed severe secondary serine deficiency [3]. In Menkes disease, they found low plasma and CSF serine in several boys with early intractable seizures and severe hypotonia, by an unknown mechanism [3]. Keularts and colleagues described two girls with fatal acute toxic encephalopathy with cerebral oedema and markedly low plasma and CSF serine, comparable to that of 3-PGDH deficiency, which was excluded clinically and, in one, by enzymology; the authors proposed a secondary deficiency due to fasting, gluconeogenesis, ketosis, and lactate [75]. Severe viral illness and encephalitis may be associated with secondary serine deficiency [3].

6.4. HSAN1 and the confusable name of serine palmitoyltransferase

HSAN1 is the most common subtype of hereditary sensory and autonomic neuropathy; it is autosomal dominant and caused by variants in SPTLC1 or SPTLC2, which encode subunits of serine palmitoyltransferase, the enzyme of the first step of de novo sphingolipid synthesis [23]. The variants alter the enzyme's specificity so that it uses alanine and glycine and forms toxic 1-deoxysphingolipids; small-fibre pain and ulcers are characteristic [85, 86]. HSAN1 is not a serine synthesis defect, but it shares with the adult forms the 1-deoxysphingolipid mechanism and a partial response to L-serine (section 7) [49, 86]. It is distinguished by autosomal dominant inheritance and by the sensory and autonomic picture with pain and limb ulcers, present in all participants in the trial by Fridman and colleagues [85, 86].

6.5. Microcephaly and ichthyosis

In the approach to congenital and postnatal microcephaly, serine synthesis and transport defects are among the treatable metabolic causes, alongside maternal phenylketonuria and defects such as PYCR2, sulfite oxidase, FOLR1, dihydrofolate reductase, SLC25A19, SEPSECS, MFSD2A, CYB5R3, ACO2, GOT2, GLUT1 and pyruvate dehydrogenase [70]. SAUD notes that the congenital microcephaly of the synthesis defects is partially reversible with early treatment [70]. Structured investigation of microcephaly includes CSF amino acids. In the approach to ichthyoses, serine synthesis defects and Neu-Laxova syndrome are among the approximately 40 metabolic disorders with ichthyosis, classified in SAUD among the ichthyoses due to complex lipid defects [70]. Debs and colleagues point out that, among the neuro-ichthyotic syndromes, Refsum disease (phytanic acid restriction) and MEDNIK syndrome (copper and zinc) also have specific treatment, and they excluded Sjögren-Larsson syndrome on the basis of normal fatty aldehyde dehydrogenase (FALDH) activity [42].

6.6. Neu-Laxova syndrome and fetal akinesia

In a fetus with akinesia, growth restriction, and contractures, the differential diagnosis of Neu-Laxova syndrome includes restrictive dermopathy, COFS syndrome, distal arthrogryposis, and ARC syndrome [72]. Fitch and colleagues distinguished classic COFS syndrome by the absence of a short neck, ichthyosis, subcutaneous oedema, and syndactyly, by less severe impairment of brain development, and by the absence of neonatal lethality [4]. Spranger and colleagues described a cerebro-arthro-digital syndrome that Scott and colleagues considered distinct from Neu-Laxova and of better prognosis [4]. Without a precise diagnosis, recurrence risks for fetal akinesia are high; when autopsy is declined, the Oxford Desk Reference proposes a limited evaluation with muscle biopsy (histology and electron microscopy) and skeletal radiographs [72]. Fetal MRI and trio exome sequencing now allow molecular diagnosis during pregnancy [55, 58].

7. Treatment and Risk Management Strategies

7.1. Principles

Targeted treatment consists of replacing the missing product: high-dose oral L-serine, combined with glycine in some patients [3]. L-serine is more effective than antiseizure medications for seizure control, and no antiseizure medication has shown specific efficacy in these disorders [3]. The stated biochemical goal is to achieve plasma and CSF serine values within the reference range [3]. Neurological efficacy depends on the timing of initiation: early treatment is necessary to prevent irreversible central nervous system injury [3]. The evidence base consists of case series and the experience of the GeneReviews authors, without randomised trials; the review by Verduci and colleagues rated the evidence for serine and glycine supplementation as level 4 on the Oxford CEBM 2011 scale (grade D) [26, 43].

7.2. L-serine: doses by phenotype and age

L-serine (the nonproprietary name; no brand name of an authorised medicinal product appears in the sources consulted) is an amino acid powder given orally, dissolved in water in the SAFE trial protocol [43, 87]. It has no FDA label or EMA summary of product characteristics for these disorders, so doses come from the literature (section 7.9).

Doses vary by a factor of about 5 between the infantile and adult forms, and the sources define no absolute maximum dose for these disorders. The SAUD drug table gives "up to 500–700 mg/d" for L-serine; the correct unit, used in SAUD's own text and in GeneReviews, is mg/kg/day [3, 23, 89]. In the setting of GRIN-related encephalopathies, a different indication, protocols used 250 mg/kg/day in 3 doses for 2 weeks and 500 mg/kg/day from week 3, not exceeding 30 g/day in patients weighing ≥60 kg [26, 90]; this ceiling has not been defined for the synthesis defects.

7.3. Glycine

Glycine (amino acid powder, oral) is added to L-serine in patients without a satisfactory response, at a dose of 200 mg/kg/day in 4–6 doses according to GeneReviews and 200–300 mg/kg/day according to SAUD [3, 23, 89]. Verduci and colleagues record 200–300 mg/kg/day in 3-PGDH deficiency and 200 mg/kg/day in PSAT deficiency, with level of evidence 4 [26]. The historical basis is the 1998 report by de Koning and colleagues: in two siblings with 3-PGDH deficiency, L-serine up to 500 mg/kg/day did not control the seizures, and the addition of glycine 200 mg/kg/day led to their complete disappearance, with gradual normalisation of the EEG over 6 months [88]. In a few patients, seizures stopped only after glycine was added [23]. Patients with mild phenotypes responded to lower doses of L-serine without glycine [23, 45]. Benke and colleagues used glycine 250 mg/kg/day, and Shen and colleagues 300 mg/kg/day in the text and 400 mg/kg/day in the table of the same article, an internal discrepancy [1, 8].

7.4. Adverse effects, tolerability, and monitoring

With high starting doses, transient acoustic startle and myoclonus were observed, which is why treatment is started at 200–400 mg/kg/day and increased gradually [3]. In the HSAN1 trial, a dose of 400 mg/kg/day was chosen because higher doses had caused reversible effects such as nausea, vomiting, nystagmus, and myoclonus [86]. The oral powder is associated with an apparently increased risk of dental caries, which warrants preventive dental care and dental evaluation every 6 months [3]. De Koning and colleagues documented no adverse effects during 3–7.5 years of follow-up of five patients [1]; Tabatabaie and colleagues observed no adverse effects over 3 years, and Debs and colleagues describe good tolerability [42, 45]. In young adults treated for many years, discontinuation of supplements was associated with psychiatric symptoms (personal communication from the GeneReviews authors), so treatment should not be interrupted [3].

The sources do not define a laboratory monitoring protocol with numerical targets and intervals. The practice described in the case reports is to adjust the dose to keep fasting plasma serine within the reference range: Byers and colleagues titrated the dose to plasma serine (96 µmol/L on treatment, with glycine 222 µmol/L), and Debs and colleagues observed initial normalisation, a decline with increased urinary serine excretion, and a return to the reference range without a dose change [13, 42]. In CSF, serine rises slowly: in the boy reported by Tabatabaie and colleagues, it rose from 9 to 29 µmol/L after 4 months [45]. EEG improvement may occur only after 6 months of L-serine [3].

7.5. Clinical response and timing of initiation

In the infantile form, seizures improve significantly with L-serine in all patients, and many become seizure free, reducing the need for long-term antiseizure medications [3]. Irritability and inconsolable crying cease within 2–3 weeks, feeding and well-being improve, and white matter volume increases, with progression of myelination in some [3, 21, 23]. SAUD describes a favourable effect on seizures, spasticity, feeding, and behaviour [23]. In one patient treated with 400 mg/kg/day, head growth stopped and infantile spasms with hypsarrhythmia appeared; with 600 and 700 mg/kg/day, head growth and the EEG normalised [21]. During 3–7.5 years of follow-up of five patients, seizure frequency decreased in all and two became seizure free, but only one, diagnosed early and treated with a high dose, made psychomotor progress [1]. High-dose oral L-serine with glycine completely resolved the ichthyosis [3].

Development depends on the timing of initiation. Patients treated prenatally or immediately after birth have normal development, and those treated from 4 months of age or later have severe delay [3, 40, 71]. The PSAT-deficient siblings of Hart and colleagues illustrate the contrast: the boy, already symptomatic, started serine 500 mg/kg/day and glycine 200 mg/kg/day at 11 weeks, with biochemical normalisation and a marginal clinical effect, and died at 7 months; his sister, with low serine and glycine at 2 hours of life, started the same regimen within the first 24 hours and had normal cranial ultrasound at 3 weeks and normal MRI at 4 months, head circumference rising from the 9th percentile at birth to the 50th–75th at 18 weeks, one apnoeic episode at 2 weeks, and normal growth and development at 3 years [6, 40]; SAUD reports a normal outcome at 15 years [23]. SAUD states that the boy started treatment at 7 weeks; the original article and OMIM give 11 weeks [6, 23, 40]. The Atlas (2020) states that no successful treatment of PSAT deficiency had been described, which the sister's case contradicts [21, 40]. In four other patients with PSAT deficiency, serine with or without glycine did not substantially improve neurodevelopment [23]. With postnatal treatment in patients with congenital microcephaly, Brassier and colleagues observed a reduction in seizures within 1 week and fewer EEG abnormalities at 1 year in the patient with PHGDH deficiency, and improved spasticity in the patient with PSAT deficiency (400–950 mg/kg/day for 5.5 years), without substantial improvement in head circumference or neurodevelopment in either [8, 77]. In the patients of Benke and colleagues, serine 500 mg/kg/day and glycine 250 mg/kg/day normalised CSF serine and glycine in two sisters, with some improvement in spasticity and responsiveness but no developmental progress; serine 400 mg/kg/day in three sisters aged 13, 19, and 21 years resolved the seizures and improved spasticity, gait, and verbal communication [1]. In the PSAT-deficient female infant of Glinton and colleagues, supplementation improved weight gain and irritability, but the delay remained profound [6]. Failure in many patients has been attributed to intrauterine serine deficiency and its effect on prenatal development [21, 38].

In the juvenile form, the two siblings of Tabatabaie and colleagues showed improved well-being, physical condition, and behaviour within weeks; the absences disappeared, the EEG remained free of epileptiform activity for 3 years, and antiseizure medications were withdrawn (ethosuximide in the boy, two drugs in the girl), with unchanged IQ (50 and 55) [45]. The authors revised the recommendations and considered 120–150 mg/kg/day probably sufficient in the mild phenotype [45]. In a 2.5-year-old Indian child homozygous for PHGDH c.1129G>A, with speech delay, seizures, microcephaly, and hyperactivity, serine and glycine supplementation controlled the seizures and allowed recovery of developmental milestones [54].

7.6. Prenatal treatment

Prenatal treatment rests on a single case published in detail [71]. In a consanguineous couple with two children severely affected by 3-PGDH deficiency with congenital microcephaly, molecular prenatal diagnosis identified an affected fetus carrying p.(Val490Met) [1, 71]. Fetal head circumference fell from the 75th percentile at 20 weeks to the 29th at 26 weeks; the mother then received L-serine 190 mg/kg/day in 3 doses from week 27, and head circumference rose to the 76th percentile at 31 weeks and was normal at birth [1, 23, 71]. Within 12 hours after birth, plasma serine fell to 33 µmol/L, with CSF depletion; MRI was normal and the EEG showed subtle epileptiform activity, which normalised within a week on L-serine 400 mg/kg/day [1]. The child had normal growth and psychomotor development at 4 years, normal MRI at 12 and 14 months, and no neurological manifestations 12 years after birth according to the Atlas and at 22 years according to SAUD [1, 21, 23]. The Atlas cites this work as "Lancet 2004;80:931," an incorrect reference; the correct one is Lancet 2004;364:2221-2 [21, 71]. OMIM describes the variant as "V90M" in that paragraph but refers to allele 606879.0001, p.(Val490Met) [1].

The status of this treatment differs between sources. GeneReviews presents it as an option for at-risk relatives with known variants, alongside starting L-serine as soon as possible after birth [3]; the GeneGuidance database classifies it as experimental, because of very limited experience and the lack of long-term follow-up of series [43]. Shaheen and Acuna-Hidalgo and colleagues proposed serine supplementation in subsequent pregnancies of couples with a child with Neu-Laxova syndrome, a proposal with no published result in the sources consulted [15, 33]. In Neu-Laxova syndrome, the anomalies are evident in the second trimester, and the effect of maternal supplementation on already established malformations has not been described [33]. In the PSAT-deficient siblings, the fetus appeared to tolerate the deficiency better than in 3-PGDH deficiency, without congenital microcephaly [40].

7.7. Adult forms

Adults with neuropathy responded partially. In the PSAT-deficient woman reported by Debs and colleagues, about 100 mg/kg/day for 3 years resolved the ichthyosis, trichorrhexis, onychodystrophy, and pruritus, resolved the hypertension (from amlodipine 10 mg twice daily with metoprolol 25 mg/day to amlodipine 5 mg/day), increased alertness and verbal communication, and kept the neuropathy stable on repeated conduction studies, without recovery [42]. In the PSP-deficient woman reported by Byers and colleagues, 4 months of treatment brought more energy, improved sensation in the feet, complete healing of the foot ulcer without recurrence, and a substantial reduction in analgesics for neuropathic pain [13, 23]. In the PHGDH-deficient adult of Méneret and colleagues, high-dose serine normalised plasma serine, with subjective functional improvement [41]. In the PSAT-deficient adolescents of Shen and colleagues, the skin was nearly normal at 3 months in one and cleared at 5 months in the other; strength improved (climbing stairs, prolonged walking), deep sensation did not improve, and nystagmus eased in one of them, without reassessment of plasma serine [8]. The authors concluded that there is no consistent dose recommendation and that the response depends on the regenerative capacity of the tissue: skin responds, nerve barely does [8].

7.8. Supportive treatment

GeneReviews organises supportive treatment by manifestation [3].

In the index patient with PSAT deficiency, clonazepam, phenytoin, paraldehyde, and thiopental did not control the seizures, and pyridoxine 120 mg/day from 10 weeks had no effect [40]. The antiseizure medications used in the juvenile form (ethosuximide and others) could be withdrawn after a response to L-serine [45]. In adults, concomitant treatment included a bisphosphonate for osteoporosis and a cochlear implant for sensorineural hearing loss, with improved comprehension [42].

7.9. Regulatory status

The L-serine and glycine used in these disorders are not medicinal products authorised for this indication. A search of the FDA orphan designation database (Office of Orphan Products Development, OOPD) on 17 October 2026, using "serine" as product and as designation and using "phosphoglycerate," returned no designation of L-serine alone for PHGDH, PSAT1, or PSPH deficiencies or for Neu-Laxova syndrome; L-serine appears only as a component of an amino acid mixture designated for phenylketonuria [25]. In the USA, L-serine is on the list of amino acids permitted as nutrient food additives (21 CFR §172.320), with a limit of 8.4% of the weight of the food's total protein for that use, which does not constitute approval as a drug [91]. In the EMA orphan designations report, there is no designation of L-serine for serine deficiency, neuropathy, or MacTel; L-serine appears only as a component of an amino acid mixture for maple syrup urine disease (EU/3/18/2076) [24]. In the EU, the Italian TAP-GRIN protocol classifies L-serine as a food for special medical purposes [92]. In INFARMED's Infomed database, a search on 26 October 2026 for "serina" and "glicina" returned no authorised medicinal product containing these substances as an oral active ingredient, so there is no Portuguese SmPC for these disorders; ANVISA's electronic drug label database was not accessible on that date (HTTP 403). With no label in any of the jurisdictions consulted, the doses in this article are those from the literature (GeneReviews, SAUD, and case series).

7.10. Clinical trials

No clinical trials are registered in ClinicalTrials.gov for serine biosynthesis deficiencies or for Neu-Laxova syndrome (search on 17 October 2026 with the terms "serine deficiency," "Neu-Laxova," PHGDH, PSAT1, and PSPH); absence of registration does not prove absence of research [3]. Information on the dose and safety of high-dose oral L-serine comes from trials in other indications.

These trials did not test L-serine in the primary synthesis deficiencies, and their populations, endpoints, and doses do not allow indirect comparisons with the case series. In the HSAN1 trial, the prespecified primary endpoint was negative, and the −1.5-point CMTNS effect comes from the longitudinal analysis in an 18-patient trial; its relevance lies in the evidence of safety of L-serine at 400 mg/kg/day for 2 years in adults and of reduction of 1-deoxysphingolipids [86]. In the SAFE trial, nonserious adverse events were more frequent with 400 than with 200 mg/kg/day (13/15 vs 9/16), and the results by lipid type have not yet been published in a journal article [87].

7.11. Developments in the past 12 months

From October 2025 to October 2026, publications on the primary deficiencies were case reports, with no trials, opinions, or authorisations [24, 25]. Luo and colleagues published the prenatal diagnosis by trio exome sequencing of PHGDH-related Neu-Laxova syndrome in a dichorionic twin (case report) [55]. Nilay and colleagues described an Indian child with PHGDH deficiency treated with serine and glycine, with seizure control and recovery of milestones (case report) [54]. Yoganathan and colleagues published a clinical image titled "serine biosynthesis defect: a treatable neurometabolic disorder" [96]. A preprint, not peer reviewed, used human genetic evidence to link serine biosynthesis to diabetic peripheral neuropathy [97]. In the regulatory and trial field for L-serine in other indications, the phase 3 MacTel trial was registered (update of 2026-01-15), the SAFE trial posted results in the registry (update of 2026-09-21), and TAP-GRIN has been recruiting since August 2025 [87, 92, 94]. Slightly outside the window, the Egyptian cohort of February 2025 proposed the founder variant PSAT1 c.734G>A (observational cohort) [58], and the 2024 mouse study showed reversibility of serine-associated retinopathy and neuropathy (preclinical) [64].

7.12. Agents and situations to avoid

GeneReviews recommends avoiding known seizure triggers: infection, physical stress, and emotional stress [3]. Discontinuation of L-serine in adults treated for many years has been associated with psychiatric symptoms [3]. Prolonged fasting reduces plasma serine and has been proposed as a cause of severe secondary deficiency in acute encephalopathies [45, 75]. The sources consulted identify no specific contraindicated drugs.

7.13. Pregnancy, lactation, perioperative care, and transition

In the pregnancy of an affected woman, experience is very limited: the GeneReviews authors are aware of pregnancies with healthy newborns, without long-term follow-up of the children, and recommend regular monitoring to keep plasma serine in the normal range with L-serine and fetal growth parameters normal [3]. In a pregnancy with an affected fetus (heterozygous mother), maternal L-serine was used from week 27 in a single documented pregnancy (section 7.6) [1, 71]. The sources consulted describe no data on lactation or perioperative protocols; the HSAN1 trial excluded pregnant and breastfeeding women and advised contraception and discontinuation of L-serine in the event of pregnancy, a precautionary measure specific to the trial [86]. In the transition from paediatric to adult care, GeneReviews recommends assessing care needs during transition and continuing treatment [3].

7.14. Guidelines and divergences

There are no published clinical practice guidelines for serine deficiencies, and searches for a guideline or consensus from SSIEM, MetabERN, ACMG, or other societies found none [3, 27]. The available recommendations diverge on specific points. For the infantile dose, GeneReviews starts at 200–400 mg/kg/day and increases to 500–700 mg/kg/day, SAUD gives 500–700 mg/kg/day in 6 doses directly, and the Atlas describes 500–700 mg/kg/day as the recommended dose [3, 21, 23]. For glycine, GeneReviews gives 200 mg/kg/day and SAUD 200–300 mg/kg/day [3, 23]. For mild forms and adults, GeneReviews and SAUD give 100–150 mg/kg/day, Tabatabaie and colleagues 120–150 mg/kg/day, and adults with neuropathy received 80–100 mg/kg/day, whereas the HSAN1 trial and the Benke sisters used 400 mg/kg/day [1, 3, 13, 23, 42, 45, 86]. For prenatal treatment, GeneReviews presents it as an option and GeneGuidance as experimental [3, 43]. For PSAT deficiency, the Atlas states that no successful treatment has been described, whereas SAUD and the original article describe a normal outcome with neonatal treatment [21, 23, 40].

8. Reproductive Options and Family Counselling

8.1. Recurrence risks

In autosomal recessive inheritance, the parents of a proband are presumed to be heterozygous, and their molecular testing is recommended to confirm carrier status and assess recurrence risk [3]. If only one parent is a carrier, with confirmed parentage, the proband may have a de novo variant or one parent may have germline mosaicism due to a postzygotic variant [3, 98]. With apparent homozygosity, a deletion of one or more exons not detected by sequencing or uniparental isodisomy should be considered [3]. Heterozygotes are asymptomatic and not at risk of the recessive disease [3]; the association data described for MacTel type 2 nevertheless indicate that PHGDH heterozygosity increases the risk of late-onset macular disease (section 2.9) [61, 62].

According to GeneReviews, siblings with biallelic variants should have a phenotype similar to that of the proband, but the timing of treatment initiation can change the course, as shown by the PSAT-deficient siblings of Hart and colleagues, and intersibling variability has been described in PHGDH deficiency [1, 3, 40, 57].

8.2. Cascade testing, carriers, and at-risk siblings

Carrier testing requires prior identification of the familial variants [3]. Evaluation of siblings has a therapeutic purpose. Newborn siblings and older and younger asymptomatic siblings should be evaluated so that L-serine can be started as early as possible; when the familial variants are known, younger siblings not tested prenatally undergo molecular testing immediately after birth and start L-serine at once if they have biallelic variants [3]. When the variants are unknown and genetic testing is not possible, biochemical testing is performed immediately after birth: some centres have reference ranges for cord blood amino acids, a less invasive test to be combined with fasting plasma serine; when this is not feasible, CSF serine is the most reliable test [3]. The window of opportunity is narrow: newborns treated in the first month have better neurological outcomes than those treated later [3]. In Ashkenazi Jewish populations, Damseh and colleagues proposed including SLC1A4 c.766G>A in carrier panels (differential) [79].

8.3. Prenatal diagnosis and preimplantation genetic testing

Once the familial variants have been identified, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic testing are possible [3]. In these disorders, prenatal diagnosis also serves to plan maternal L-serine treatment during pregnancy and the start of L-serine as soon as possible after birth [3, 40, 71]. The optimal time to determine genetic risk and discuss prenatal or preimplantation diagnosis is before pregnancy, and counselling should be offered to young adults who are carriers or at risk [3]. Differing perspectives exist on the use of prenatal diagnosis and should be discussed [3]. In families with undiagnosed fetal akinesia, recurrence risks are high and efforts should focus on a precise diagnosis, by autopsy or, when it is declined, by limited evaluation, and by exome sequencing [72]. In the family reported by Bourque and colleagues, recurrence manifested as increased nuchal translucency or cystic hygroma in three pregnancies, with five unstudied first-trimester losses [4].

8.4. Counselling of minors and content of the consultation

Testing of asymptomatic minor siblings is justified by the direct therapeutic benefit of early diagnosis, which distinguishes these disorders from untreatable conditions [3]. For carrier status, which has no therapeutic consequence, GeneReviews proposes offering counselling to young adults who are carriers or at risk [3]. The consultation should address the nature of the disease, the mode of inheritance, the risks to siblings and offspring, the possibility of prenatal and neonatal treatment, the limited published experience with maternal treatment, and, for PHGDH carriers, the association with MacTel [3, 61].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Prevalence and what each figure measures

There is no validated estimate of the population prevalence or incidence of serine biosynthesis deficiencies [3]. The available figures are counts of patients published or known to the authors, which measure different things and are not interchangeable.

The Orphanet counts are lower than those of SAUD and GeneReviews because they reflect different time periods and criteria; none is a prevalence [16, 23]. The MedlinePlus page, last updated in 2014, states "at least 15 cases" of PHGDH deficiency and is outdated [99]. Shaheen and colleagues suggested a referral bias: patients at the severe end are seen by dysmorphologists and rarely studied metabolically, and no previous report of Neu-Laxova explicitly described plasma amino acids [33]. The true distribution by gene and phenotype may therefore differ from that of the published series.

9.2. Geography, ancestry, and founder effect

In the USA, reports include the adults with PSAT deficiency evaluated in the NIH Undiagnosed Diseases Program (Chinese/Taiwanese ancestry) and with PSP deficiency in Seattle (Polish and Northern European ancestry), the families of Benke and colleagues, and the children in the metabolomic series of Glinton and colleagues [1, 13, 42, 48]. In Europe, patients come from Belgium, the Netherlands, France, Spain, and the United Kingdom: the first patients with 3-PGDH and PSP deficiency, the Dutch siblings with the juvenile form, Méneret's French adult, Brassier's patients, Pineda's Moroccan family with West syndrome, Serrano Olave's prenatal diagnosis, and the British siblings with PSAT deficiency [20, 35, 37, 40, 41, 45, 53, 77]. PHGDH p.(Val490Met) is the best-documented variant in Europe and Turkey, with recurrent origin at a CpG dinucleotide, and it has also been found in Ashkenazi individuals, with one heterozygote in 400 [38, 52].

Populations with high rates of consanguinity account for a concentration of Neu-Laxova syndrome: Saudi Arabia (PHGDH p.(Gly140Arg) with a shared haplotype, p.(Arg163Gln)), Iran and Turkey (founder PSAT1 c.296C>T), Egypt (PSAT1 c.734G>A proposed as a founder variant in 12 families, and two Egyptian families described in 1991 with four other affected members each), Jordan, Pakistan (PSPH c.103G>A), and the United Arab Emirates [1, 4, 15, 33, 58, 59]. In China, reports include siblings with PHGDH p.(Val404Asp), two adolescents homozygous for PSAT1 p.(Ala15Pro) (gnomAD frequency of 12/367,166 alleles), and fetuses with loss of the PHGDH initiation codon [4, 8, 57]. In the Ashkenazi Jewish population, the differential SLC1A4 c.766G>A has a carrier frequency close to 1% [78, 79].

In Brazil, Mattos and colleagues described very severe Neu-Laxova syndrome with homozygous PHGDH c.1297C>T p.(Gln433Ter), in a child of first-cousin parents, with symmetric growth restriction, microcephaly, vermian hypoplasia, micrognathia, hydrops, short limbs, arthrogryposis, and clubfoot, confirmed by prenatal MRI [56]. Cavole and colleagues reported a Brazilian stillborn infant with Neu-Laxova and a novel missense variant in PHGDH, with consanguineous parents [100]. The sources consulted include no data from Portugal. The absence of data in these sources does not demonstrate an absence of patients in these countries.

9.3. Special populations

In affected pregnant women, monitoring of plasma serine and fetal growth is the only guidance available (section 7.13) [3]. In fetuses, maternal treatment has been described in one case (section 7.6) [71]. In at-risk newborns, serine and glycine are already low at 2 hours of life [40]. In adults, late diagnosis is associated with its own complications: osteoporosis, primary ovarian insufficiency, sensorineural hearing loss, and neuropathic ulcers with osteomyelitis and amputations [13, 42]. Adults with intellectual disability and polyneuropathy have transition needs and require long-term social support [3].

9.4. Reference networks and patient organisations

In Europe, the relevant European Reference Network is MetabERN, through its amino acid and organic acid–related disorders subnetwork [27]. ERN ITHACA covers rare congenital malformations and intellectual disability, which is relevant to Neu-Laxova syndrome, and ERN-Skin covers the ichthyoses [28, 29]. GeneReviews lists as resources the MedlinePlus page and the Dutch patient association for inborn errors of metabolism (Patiëntenvereniging voor Stofwisselingsziekten) [3, 99]. The National Organization for Rare Disorders (NORD) has a page on PHGDH deficiency with a definition, synonyms, and links, but no dedicated report [101]. The GeneReviews authors make themselves available for diagnostic questions and variant review [3].

10. Illustrative Clinical Case

In 2021, Debs and colleagues, from the Undiagnosed Diseases Program of the National Institutes of Health (NIH, USA), published in the American Journal of Medical Genetics Part A the first adult with phosphoserine aminotransferase deficiency to be diagnosed and treated [42]. The patient, a woman of Chinese/Taiwanese ancestry, was born at term with intrauterine growth restriction (weight at the 8th percentile), microcephaly, and dry, scaling skin; her mother had had two first-trimester miscarriages and a stillbirth [42]. She attended special education and underwent surgery for esotropia at 8 years. At 13 years, walking difficulties appeared, requiring a walking frame and, by mid-adolescence, a wheelchair; around age 20, contractures and sensorineural hearing loss developed; the ichthyosis worsened in late adolescence, with refractory generalised pruritus [6, 42]. Muscle biopsy at 14 years showed predominant type II fibre atrophy, and sural nerve biopsy showed near-complete loss of myelinated axons; Sjögren-Larsson syndrome was excluded by normal FALDH activity [42].

Evaluated in the programme from age 34, at 38 years she had a head circumference of 50.6 cm (below the 1st percentile, −3.5 standard deviations), micrognathia, and a depressed nasal bridge; bilateral macular lesions (white dots of about 300 µm) with preserved vision; spastic dysarthria; severe to profound bilateral sensorineural hearing loss with absent otoacoustic emissions; spastic tetraparesis with fixed contractures of the hands, hips, knees, and ankles, and distal atrophy and weakness with preserved proximal upper-limb strength; areflexia; and distal loss of pain and temperature sensation, with absent vibration sense even at the proximal joints [42]. The skin showed generalised xerosis with fine scaling, most marked on the forearms, hands, lower abdomen, and thighs, with nail dystrophy, trichoschisis and trichorrhexis nodosa, and patchy occipital alopecia [42]. MRI showed stable atrophy and EEG showed diffuse bursts of theta and delta activity [42].

Fasting plasma serine was 21 µmol/L (reference 63–187), with normal glycine (160 µmol/L; 126–490); a nonfasting sample at 26 years had shown 43 µmol/L, just below the limit (44–180). In CSF, serine was 3.8 µmol/L (18.3–52.2), with normal glycine, low 5-hydroxyindoleacetic acid (5-HIAA) of 41 nmol/L (67–140) and low homovanillic acid of 102 nmol/L (145–324), and normal 5-methyltetrahydrofolate [42]. Exome sequencing identified compound heterozygosity in PSAT1 (NM_058179.4): c.467C>T p.(Thr156Met) and c.43G>C p.(Ala15Pro) [19, 42].

At 37 years, she started oral L-serine at about 100 mg/kg/day (1.5 g 3 times daily), a dose extrapolated from paediatric cases and from adults with HSAN1 [42]. Plasma serine normalised, then fell with increased urinary serine excretion, and returned to the reference range without a dose change; CSF serine on treatment could not be measured because of spinal canal stenosis [42]. Over 3 years, the ichthyosis, trichorrhexis, onychodystrophy, and pruritus resolved; the arterial hypertension resolved, with a reduction in antihypertensive medication; the patient became more alert and vocal; and the neuropathy, already severe at baseline, remained stable on repeated conduction studies [42]. She had three spontaneous menstrual periods in 7 months but was diagnosed with primary ovarian insufficiency at 39 years, with follicle-stimulating hormone (FSH) in the menopausal range and undetectable inhibin B and anti-Müllerian hormone; karyotype, FMR1 premutation testing, and anti-adrenal antibodies were negative, and serine deficiency was not excluded as the cause [42]. She was treated with a bisphosphonate for osteoporosis (femoral T-score −3.6) and received a right cochlear implant, with improved comprehension [42]. Figure 2 of the article shows the skin and nails before (2013) and after treatment (2018): https://pmc.ncbi.nlm.nih.gov/articles/PMC8330494/figure/F2/ [42].

The case illustrates three points. First, a congenital defect of serine biosynthesis can reach adulthood undiagnosed, presenting with neuropathy, ichthyosis, and intellectual disability. Second, nonfasting plasma serine may be only slightly below the limit, and CSF analysis and genetic testing are decisive. Third, in adults, L-serine acts mainly on tissues with regenerative capacity (skin, hair, and nails) and stabilises the neuropathy without reversing it. The dose used (about 100 mg/kg/day) is consistent with the 100–150 mg/kg/day recommended by GeneReviews for adolescents and adults, but it comes from a single case, and this patient's gynaecological, bone, and hearing follow-up reflects her complications rather than an established protocol [3, 42]. A complementary case, of two Chinese boys homozygous for PSAT1 p.(Ala15Pro) with juvenile-onset neuropathy, shows resolution of ichthyosis within 3–5 months on L-serine and glycine (Figure 2 of the article: https://pmc.ncbi.nlm.nih.gov/articles/PMC9428789/figure/F2/) [8].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis

Prognosis depends on the phenotype and on the timing of treatment initiation. In Neu-Laxova syndrome, most fetuses are stillborn or die in the immediate neonatal period from respiratory failure or sepsis secondary to the skin lesions; survival up to 2 months has been described in the molecular series and, in one infant with a mild form, beyond 10 months [3, 32, 33]. In the review of 31 patients with PSAT deficiency, 18 died at birth or in the first month [8]. In the untreated or late-treated infantile form, development plateaus in the first year, with a developmental age of about 1 year even in patients described up to age 24 [3, 23]. With treatment from 4 months of age, patients function at a preschool level in adulthood; with treatment prenatally or immediately after birth, development is normal, with a maximum published follow-up of 22 years (prenatal treatment) and 15 years (neonatal treatment in PSAT deficiency) [3, 23]. Long-term survival is the rule in 3-PGDH deficiency with congenital microcephaly [40]. The PSAT-deficient patient treated after becoming symptomatic died at 7 months, and one of the first patients with 3-PGDH deficiency died at 5 years of unrelated infectious complications [38, 40]. In the juvenile form, cognition remains in the mildly impaired to normal range, with improved behaviour and seizure control on treatment, and many develop spastic tetraparesis [3, 45]. In the adult form, the polyneuropathy is progressive without treatment, and supplementation stabilises it and resolves the skin lesions without restoring lost function [8, 42]. The sources do not allow life expectancy to be estimated for the nonlethal forms.

11.2. Initial evaluation after diagnosis

11.3. Surveillance

GeneReviews defines no numerical serine targets beyond the reference range, nor the frequency of serine measurement, MRI, or EEG [3]. Intervals flagged as not defined reflect practice reported in case reports, not validated recommendations.

12. Summary and Concluding Remarks

Serine biosynthesis deficiencies are three autosomal recessive inborn errors of the phosphorylated pathway of de novo L-serine synthesis, caused by biallelic variants in PHGDH (about 69% of patients), PSPH (25%), and PSAT1 (6%), with more than 50 patients with a molecular diagnosis reported and a prevalence below 1/1,000,000 according to Orphanet. Serine deficiency in the brain, which depends on local synthesis in astrocytes, impairs neuronal proliferation, phospholipid and sphingolipid synthesis, the one-carbon unit pool, and the production of D-serine and glycine, coagonists of the NMDA receptor. The clinical spectrum is continuous: Neu-Laxova syndrome, with severe fetal growth restriction, microcephaly, ichthyosis, oedema, and contractures, and prenatal or neonatal lethality in most; the infantile form, with congenital microcephaly, refractory epilepsy, spastic tetraplegia, cataracts, and hypomyelination; the juvenile form, with absences and mild intellectual disability; and the adult form, with an axonal polyneuropathy resembling Charcot-Marie-Tooth disease type 2, sometimes with ichthyosis. All presentations occur with any of the three genes, and residual enzyme activity in fibroblasts does not predict severity.

Diagnosis rests on low CSF serine, usually below 13 µmol/L, interpreted against age-specific reference ranges, and on plasma serine collected in the fasting state, because postprandial values may be normal; it is confirmed by identifying biallelic variants, with the caveats that sequencing may miss intragenic deletions and that low serine also occurs in secondary deficiencies, such as GOT2 deficiency, complex I defects, Menkes disease, and acute encephalopathies. The main differential of the infantile form is ASCT1 transporter deficiency (SLC1A4), with progressive postnatal microcephaly and normal biochemistry; that of the adult form is autosomal dominant HSAN1; and PHGDH heterozygosity is associated with MacTel type 2.

Treatment is oral L-serine, started at 200–400 mg/kg/day and increased to 500–700 mg/kg/day in 4–6 doses in the infantile forms, with 100–150 mg/kg/day in mild forms and adults, and glycine 200–300 mg/kg/day as an adjunct. L-serine controls seizures better than antiseizure medications and resolves ichthyosis, but only treatment initiated prenatally or immediately after birth has allowed normal development; patients treated from 4 months of age remain severely delayed. Maternal treatment with 190 mg/kg/day from week 27 normalised fetal head growth in one case, with normal development at 22 years. L-serine is not an authorised medicinal product and has no orphan designation for these disorders in the USA or the EU, there are no registered trials or society guidelines, and doses come from GeneReviews and from case series at evidence level 4. The clinical priorities are early recognition, immediate evaluation of newborn siblings, and reproductive counselling that includes the possibility of prenatal diagnosis with maternal treatment.

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