Pathogenic PSAT1 variants and autosomal recessive axonal Charcot–Marie–Tooth disease with ichthyosis



      Biallelic pathogenic phosphoserine aminotransferase 1 (PSAT1) variants generally cause a severe phenotype predominantly involving central nervous system. Here, for the first time, we report two patients harboring pathogenic PSAT1 variants only manifested as polyneuropathy and ichthyosis.


      Two patients from unrelated families presenting with polyneuropathy and ichthyosis were enrolled. Whole exome sequencing was performed to identify possible disease-causing variants. Their clinical, electrophysiological, imaging, biochemical, and pathological changes were in detail assessed and investigated.


      Homozygous variants c.43G>C and compound heterozygous variants c.112A>C and c.43G>C in PSAT1 were identified in the patients 1 and 2, respectively. Nerve conduction studies revealed preserved or mildly slow of motor nerve conduction velocities of the median nerves in the two patients, while the compound motor action potential in patient 1 was severely decreased. Brain MRI of the two patients found no abnormalities. Median nerve enlargement was observed on ultrasound in patient 1. Both patients had normal level of serine and glycine in plasma and cerebrospinal fluid. Sural nerve biopsy found severe loss of myelinated fibers. Electron microscopy revealed neurofilaments accumulation and mitochondrial aggregation in axons. Both variants in PSAT1 were classified as likely pathogenic or pathogenic variants according to the standard guidelines.


      Our study confirms that pathogenic PSAT1 variants can cause a mild phenotype, predominantly as autosomal recessive axonal Charcot–Marie–Tooth disease.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to Pediatric Neurology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • de Koning T.J.
        • Snell K.
        • Duran M.
        • Berger R.
        • Poll-The B.T.
        • Surtees R.
        L-serine in disease and development.
        The Biochemical journal. 2003; 371: 653-661
        • Tabatabaie L.
        • Klomp L.W.
        • Rubio-Gozalbo M.E.
        • et al.
        Expanding the clinical spectrum of 3-phosphoglycerate dehydrogenase deficiency.
        Journal of inherited metabolic disease. 2011; 34: 181-184
        • Hart C.E.
        • Race V.
        • Achouri Y.
        • et al.
        Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway.
        American journal of human genetics. 2007; 80: 931-937
        • Debs S.
        • Ferreira C.R.
        • Groden C.
        • et al.
        Adult diagnosis of congenital serine biosynthesis defect: A treatable cause of progressive neuropathy.
        American journal of medical genetics. Part A. 2021; 185: 2102-2107
        • Pareyson D.
        • Marchesi C.
        Diagnosis, natural history, and management of Charcot-Marie-Tooth disease.
        Lancet Neurol. 2009; 8: 654-667
        • Pipis M.
        • Rossor A.M.
        • Laura M.
        • Reilly M.M.
        Next-generation sequencing in Charcot-Marie-Tooth disease: opportunities and challenges.
        Nat Rev Neurol. 2019; 15: 644-656
        • O'Bryan R.
        • Kincaid J.
        Nerve Conduction Studies: Basic Concepts and Patterns of Abnormalities.
        Neurol Clin. 2021; 39: 897-917
        • Meng L.
        • Fu J.
        • Lv H.
        • Zhang W.
        • Wang Z.
        • Yuan Y.
        Novel mutations in HINT1 gene cause autosomal recessive axonal neuropathy with neuromyotonia in two cases of sensorimotor neuropathy and one case of motor neuropathy.
        Neuromuscul Disord. 2018; 28: 646-651
        • Yu J.
        • Luan X.H.
        • Yu M.
        • et al.
        GGC repeat expansions in NOTCH2NLC causing a phenotype of distal motor neuropathy and myopathy.
        Ann Clin Transl Neurol. 2021; 8: 1330-1342
        • Richards S.
        • Aziz N.
        • Bale S.
        • et al.
        Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
        Genet Med. 2015; 17: 405-424
        • Li Q.
        • Wang K.
        InterVar: Clinical Interpretation of Genetic Variants by the 2015 ACMG-AMP Guidelines.
        American journal of human genetics. 2017; 100: 267-280
        • Waterhouse A.
        • Bertoni M.
        • Bienert S.
        • et al.
        SWISS-MODEL: homology modelling of protein structures and complexes.
        Nucleic acids research. 2018; 46: W296-w303
        • Bienert S.
        • Waterhouse A.
        • de Beer T.A.
        • et al.
        The SWISS-MODEL Repository-new features and functionality.
        Nucleic acids research. 2017; 45: D313-d319
        • Ma J.
        • Wang Z.
        • Song Y.
        • Hu P.
        • Zhang B.
        BMI percentile curves for Chinese children aged 7-18 years, in comparison with the WHO and the US Centers for Disease Control and Prevention references.
        Public health nutrition. 2010; 13: 1990-1996
        • Sirr A.
        • Lo R.S.
        • Cromie G.A.
        • et al.
        A yeast-based complementation assay elucidates the functional impact of 200 missense variants in human PSAT1.
        Journal of inherited metabolic disease. 2020; 43: 758-769
        • Acuna-Hidalgo R.
        • Schanze D.
        • Kariminejad A.
        • et al.
        Neu-Laxova syndrome is a heterogeneous metabolic disorder caused by defects in enzymes of the L-serine biosynthesis pathway.
        American journal of human genetics. 2014; 95: 285-293
        • El-Hattab A.W.
        • Shaheen R.
        • Hertecant J.
        • et al.
        On the phenotypic spectrum of serine biosynthesis defects.
        Journal of inherited metabolic disease. 2016; 39: 373-381
        • Brassier A.
        • Valayannopoulos V.
        • Bahi-Buisson N.
        • et al.
        Two new cases of serine deficiency disorders treated with l-serine.
        European journal of paediatric neurology : EJPN : official journal of the European Paediatric Neurology Society. 2016; 20: 53-60
        • Glinton K.E.
        • Benke P.J.
        • Lines M.A.
        • et al.
        Disturbed phospholipid metabolism in serine biosynthesis defects revealed by metabolomic profiling.
        Molecular genetics and metabolism. 2018; 123: 309-316
        • Ni C.
        • Cheng R.H.
        • Zhang J.
        • et al.
        Novel and recurrent PHGDH and PSAT1 mutations in Chinese patients with Neu-Laxova syndrome.
        European journal of dermatology : EJD. 2019; 29: 641-646
        • Abdelfattah F.
        • Kariminejad A.
        • Kahlert A.K.
        • et al.
        Expanding the genotypic and phenotypic spectrum of severe serine biosynthesis disorders.
        Human mutation. 2020; 41: 1615-1628
        • Shapira Zaltsberg G.
        • McMillan H.J.
        • Miller E.
        Phosphoserine aminotransferase deficiency: imaging findings in a child with congenital microcephaly. The journal of maternal-fetal & neonatal medicine : the official journal of the European.
        Association of Perinatal Medicine, the Federation of Asia and Oceania Perinatal Societies, the International Society of Perinatal Obstet. 2020; 33: 1033-1035
        • Byers H.M.
        • Bennett R.L.
        • Malouf E.A.
        • et al.
        Novel Report of Phosphoserine Phosphatase Deficiency in an Adult with Myeloneuropathy and Limb Contractures.
        JIMD Rep. 2016; 30: 103-108
        • Méneret A.
        • Wiame E.
        • Marelli C.
        • Lenglet T.
        • Van Schaftingen E.
        • Sedel F.
        A serine synthesis defect presenting with a Charcot-Marie-Tooth-like polyneuropathy.
        Arch Neurol. 2012; 69: 908-911
        • El-Hattab A.W.
        Serine biosynthesis and transport defects.
        Molecular genetics and metabolism. 2016; 118: 153-159
        • de Koning T.J.
        • Klomp L.W.
        Serine-deficiency syndromes.
        Current opinion in neurology. 2004; 17: 197-204
        • Jani-Acsadi A.
        • Ounpuu S.
        • Pierz K.
        • Acsadi G.
        Pediatric Charcot-Marie-Tooth disease.
        Pediatr Clin North Am. 2015; 62: 767-786
        • Gallardo E.
        • Noto Y.
        • Simon N.G.
        Ultrasound in the diagnosis of peripheral neuropathy: structure meets function in the neuromuscular clinic.
        J Neurol Neurosurg Psychiatry. 2015; 86: 1066-1074
        • Vallat J.M.
        • Ouvrier R.A.
        • Pollard J.D.
        • et al.
        Histopathological findings in hereditary motor and sensory neuropathy of axonal type with onset in early childhood associated with mitofusin 2 mutations.
        J Neuropathol Exp Neurol. 2008; 67: 1097-1102
        • de Koning T.J.
        • Duran M.
        • Dorland L.
        • et al.
        Beneficial effects of L-serine and glycine in the management of seizures in 3-phosphoglycerate dehydrogenase deficiency.
        Annals of neurology. 1998; 44: 261-265
        • Sandler M.
        • Karoum F.
        • Ruthven C.R.
        • Calne D.B.
        m-Hydroxyphenylacetic acid formation from L-dopa in man: suppression by neomycin.
        Science (New York, N.Y.). 1969; 166: 1417-1418
        • Xiong X.
        • Liu D.
        • Wang Y.
        • Zeng T.
        • Peng Y.
        Urinary 3-(3-Hydroxyphenyl)-3-hydroxypropionic Acid, 3-Hydroxyphenylacetic Acid, and 3-Hydroxyhippuric Acid Are Elevated in Children with Autism Spectrum Disorders.
        BioMed research international. 2016; 20169485412
        • Kawase T.
        • Nagasawa M.
        • Ikeda H.
        • Yasuo S.
        • Koga Y.
        • Furuse M.
        Gut microbiota of mice putatively modifies amino acid metabolism in the host brain.
        Br J Nutr. 2017; 117: 775-783
        • Bi H.
        • Gao Y.
        • Yao S.
        • Dong M.
        • Headley A.P.
        • Yuan Y.
        Hereditary sensory and autonomic neuropathy type I in a Chinese family: British C133W mutation exists in the Chinese.
        Neuropathology. 2007; 27: 429-433
        • Suriyanarayanan S.
        • Othman A.
        • Dräger B.
        • et al.
        A Novel Variant (Asn177Asp) in SPTLC2 Causing Hereditary Sensory Autonomic Neuropathy Type 1C.
        Neuromolecular Med. 2019; 21: 182-191
        • Shaheen R.
        • Rahbeeni Z.
        • Alhashem A.
        • et al.
        Neu-Laxova syndrome, an inborn error of serine metabolism, is caused by mutations in PHGDH.
        American journal of human genetics. 2014; 94: 898-904
        • Takeichi T.
        • Okuno Y.
        • Kawamoto A.
        • et al.
        Reduction of stratum corneum ceramides in Neu-Laxova syndrome caused by phosphoglycerate dehydrogenase deficiency.
        Journal of lipid research. 2018; 59: 2413-2420
        • Heggar Venkataramana S.
        • Puttaswamy N.
        • Kodimule S.
        Potential benefits of oral administration of AMORPHOPHALLUS KONJAC glycosylceramides on skin health - a randomized clinical study.
        BMC complementary medicine and therapies. 2020; 20: 26
        • Leyvraz C.
        • Charles R.P.
        • Rubera I.
        • et al.
        The epidermal barrier function is dependent on the serine protease CAP1/Prss8.
        The Journal of cell biology. 2005; 170: 487-496