Two new cases of serine deficiency disorders treated with l-serine

Brassier, Anaïs; Valayannopoulos, Vassili; Bahi‐Buisson, Nadia; Wiame, Elsa; Hubert, Laurence; Boddaert, Nathalie; Kamińska, Anna; Habarou, Florence; Desguerre, Isabelle; Schaftingen, Emile Van; Ottolenghi, Chris; Lonlay, Pascale de

doi:10.1016/j.ejpn.2015.10.007

Cited by 38 publications

(42 citation statements)

References 19 publications

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“…The same is true for associated EEG abnormalities; both hypsarithmia and multifocal seizure activity evolving towards Lennox-Gastaut syndrome have been observed. Although the clinical seizures can respond rapidly to therapy (within weeks), normalization or improvement of EEG abnormalities may take much longer, in some cases as long as 6–12 months (de Koning et al 1998; Brassier et al 2016). Cranial MRI in patients with serine deficiency shows a profound decrease of cerebral white matter volume due to hypomyelination (de Koning et al 2000).…”

Section: Serine Deficiencymentioning

confidence: 99%

“…Unfortunately, amino acid therapy does not have a positive effect on psychomotor development in symptomatic patients even when their seizures are responding. No progress, or only very limited progress, in psychomotor development has been observed during (long term) treatment follow-up (de Koning et al 2002; Brassier et al 2016; personal observations). However, treatment can be successful when amino acid therapy is initiated before symptoms arise, either as antenatal L-serine therapy given to the mother or as immediate postnatal therapy on the first day of life in still asymptomatic patients (de Koning et al 2004; Hart et al 2007).…”

Section: Serine Deficiencymentioning

confidence: 99%

“…It is important to recognize that congenital microcephaly and seizures are not obligatory. Some children present first with severe psychomotor disability accompanied by secondary microcephaly and failure to thrive (Brassier et al 2016). One of the other symptoms regularly seen in infants is congenital cataracts (Tabatabaie et al 2010).…”

Section: Infantile Serine Deficiency Phenotypementioning

confidence: 99%

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Amino acid synthesis deficiencies

Koning

2017

J of Inher Metab Disea

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In recent years the number of disorders known to affect amino acid synthesis has grown rapidly. Nor is it just the number of disorders that has increased: the associated clinical phenotypes have also expanded spectacularly, primarily due to the advances of next generation sequencing diagnostics. In contrast to the “classical” inborn errors of metabolism in catabolic pathways, in which elevated levels of metabolites are easily detected in body fluids, synthesis defects present with low values of metabolites or, confusingly, even completely normal levels of amino acids. This makes the biochemical diagnosis of this relatively new group of metabolic diseases challenging. Defects in the synthesis pathways of serine metabolism, glutamine, proline and, recently, asparagine have all been reported. Although these amino acid synthesis defects are in unrelated metabolic pathways, they do share many clinical features. In children the central nervous system is primarily affected, giving rise to (congenital) microcephaly, early onset seizures and varying degrees of mental disability. The brain abnormalities are accompanied by skin disorders such as cutis laxa in defects of proline synthesis, collodion-like skin and ichthyosis in serine deficiency, and necrolytic erythema in glutamine deficiency. Hypomyelination with accompanying loss of brain volume and gyration defects can be observed on brain MRI in all synthesis disorders. In adults with defects in serine or proline synthesis, spastic paraplegia and several forms of polyneuropathy with or without intellectual disability appear to be the major symptoms in these late-presenting forms of amino acid disorders. This review provides a comprehensive overview of the disorders in amino acid synthesis.

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Section: Serine Deficiencymentioning

confidence: 99%

Section: Serine Deficiencymentioning

confidence: 99%

Section: Infantile Serine Deficiency Phenotypementioning

confidence: 99%

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Amino acid synthesis deficiencies

Koning

2017

J of Inher Metab Disea

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“…with the intermediate clinical expression has been published before with a similar phenotype of serine biosynthesis deficiency with severe prenatal onset microcephaly (Brassier et al, 2016 with a severe form of nonlethal PSAT1 deficiency. The highest level, still significantly below the normal, was calculated for p.Asp100Ala, a variant known to be associated with nonlethal PSAT1 deficiency (Sirr et al, 2020).…”

Section: Discussionmentioning

confidence: 95%

Expanding the genotypic and phenotypic spectrum of severe serine biosynthesis disorders

Abdelfattah

Kariminejad²,

Kahlert

et al. 2020

Human Mutation

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Serine biosynthesis disorders comprise a spectrum of very rare autosomal recessive inborn errors of metabolism with wide phenotypic variability. Neu–Laxova syndrome represents the most severe expression and is characterized by multiple congenital anomalies and pre‐ or perinatal lethality. Here, we present the mutation spectrum and a detailed phenotypic analysis in 15 unrelated families with severe types of serine biosynthesis disorders. We identified likely disease‐causing variants in the PHGDH and PSAT1 genes, several of which have not been reported previously. Phenotype analysis and a comprehensive review of the literature corroborates the evidence that serine biosynthesis disorders represent a continuum with varying degrees of phenotypic expression and suggest that even gradual differences at the severe end of the spectrum may be correlated with particular genotypes. We postulate that the individual residual enzyme activity of mutant proteins is the major determinant of the phenotypic variability, but further functional studies are needed to explore effects at the enzyme protein level.

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“…Treatment with high oral doses of L-serine and, if insufficient to achieve seizure control, L-glycine has a positive effect on epilepsy and spasticity in individuals with serine deficiency. The same treatment fails to improve neurocognitive development if it is started after the onset of symptoms (de Koning et al 2002;Brassier et al 2016). Noteworthy, antenatal L-serine therapy initiated presymptomatically or immediate postnatal therapy significantly improves therapeutic efficacy (de Koning et al 2004;Hart et al 2007).…”

Section: Serine Deficiency Syndromesmentioning

confidence: 99%

Metabolism of amino acid neurotransmitters: the synaptic disorder underlying inherited metabolic diseases

Kölker

2018

J of Inher Metab Disea

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Amino acids are involved in various metabolic pathways and some of them also act as neurotransmitters. Since biosynthesis of L-glutamate and γ-aminobutyric acid (GABA) requires 2-oxoglutarate while 3-phosphoglycerate is the precursor of L-glycine and D-serine, evolutionary selection of these amino acid neurotransmitters might have been driven by their capacity to provide important information about the glycolytic pathway and Krebs cycle. Synthesis and recycling of amino acid neurotransmitters as well as composition and function of their receptors are often compromised in inherited metabolic diseases. For instance, increased plasma L-phenylalanine concentrations impair cerebral biosynthesis of protein and bioamines in phenylketonuria, while elevated cerebral L-phenylalanine directly acts via ionotropic glutamate receptors. In succinic semialdehyde dehydrogenase deficiency, the neurotransmitter GABA and neuromodulatory γ-hydroxybutyric acid are elevated. Chronic hyperGABAergic state results in progressive downregulation of GABA and GABA receptors and impaired mitophagy. In glycine encephalopathy, the neurological phenotype is precipitated by L-glycine acting both via cortical NMDA receptors and glycine receptors in spinal cord and brain stem neurons. Serine deficiency syndromes are biochemically characterized by decreased biosynthesis of L-serine, an important neurotrophic factor, and the neurotransmitters D-serine and L-glycine. Supplementation with L-serine and L-glycine has a positive effect on seizure frequency and spasticity, while neurocognitive development can only be improved if treatment starts in utero or immediately postnatally. With novel techniques, the study of synaptic dysfunction in inherited metabolic diseases has become an emerging research field. More and better therapies are needed for these difficult-to-treat diseases.

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Two new cases of serine deficiency disorders treated with l-serine

Cited by 38 publications

References 19 publications

Amino acid synthesis deficiencies

Amino acid synthesis deficiencies

Expanding the genotypic and phenotypic spectrum of severe serine biosynthesis disorders

Metabolism of amino acid neurotransmitters: the synaptic disorder underlying inherited metabolic diseases

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