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A Serine Synthesis Defect Presenting With a Charcot-Marie-Tooth–Like Polyneuropathy FREE

Aurélie Méneret, MD; Elsa Wiame, PhD; Cecilia Marelli, MD; Timothée Lenglet, MD; Emile Van Schaftingen, MD, PhD; Frédéric Sedel, MD, PhD
[+] Author Affiliations

Author Affiliations: Departments of Neurology (Drs Méneret and Sedel), Genetics (Dr Marelli), and Clinical Neurophysiology (Dr Lenglet), Pitié-Salpêtrière Hospital, Assistance Publique des Hôpitaux de Paris, Paris, France; and de Duve Institute, Université Catholique de Louvain, Brussels, Belgium (Drs Wiame and Van Schaftingen). Dr Marelli is now with the Department of Neurology, Gui de Chauliac Hospital, Montpellier, France.


Arch Neurol. 2012;69(7):908-911. doi:10.1001/archneurol.2011.1526.
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Background Serine synthesis defects, characterized by developmental delay and seizures, have been described in children.

Objective To describe a case of serine synthesis defect due to 3-phosphoglycerate dehydrogenase deficiency in an adult with prominent chronic polyneuropathy.

Design Case report.

Setting Neurologic referral center.

Patient A 31-year-old man with congenital cataracts, mild psychomotor retardation, slight cerebellar ataxia, and chronic axonal sensorimotor polyneuropathy.

Interventions Electrophysiologic, metabolic, and genetic testing and treatment with oral L-serine.

Main Outcome Measures Serine values in plasma and cerebrospinal fluid and clinical examination.

Results Amino acid analysis showed low serine levels in plasma and cerebrospinal fluid, and genetic analysis revealed 2 heterozygous mutations in the PGDH gene. Treatment with high-dose serine resulted in normalization of plasma serine values and subjective functional improvement.

Conclusions This case expands the phenotypic spectrum of 3-phosphoglycerate dehydrogenase deficiency. Plasma amino acid chromatography should be added to the list of investigations performed in patients with Charcot-Marie-Tooth–like polyneuropathy, especially if it is associated with psychomotor delay and congenital cataracts.

Figures in this Article

L-Serine is a nonessential amino acid whose biosynthesis via the phosphorylated pathway is known to play an essential role in the central nervous system.1 Three enzymes are involved in this pathway: 3-phosphoglycerate dehydrogenase (3-PGDH), phosphoserine aminotransferase, and phosphoserine phosphatase (Figure 1). Serine synthesis defects caused by deficiencies in each of these 3 enzymes, most of which were caused by 3-PGDH deficiency, have been reported in children.2 Although 3-PGDH deficiency was first described 15 years ago,3 only a dozen cases have been reported to date, with 2 clinical forms described: an infantile form, characterized by severe encephalopathy with microcephaly and intractable epilepsy, and a juvenile form, with milder developmental delay and seizures.4 Herein, we report a novel presentation of 3-PGDH deficiency in an adult with prominent Charcot-Marie-Tooth–like polyneuropathy.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. The phosphorylated L-serine biosynthesis pathway. 3-PGDH indicates 3-phosphoglycerate dehydrogenase; PSAT, phosphoserine aminotransferase; PSPH, phosphoserine phosphatase; and SHMT, serine hydroxymethyltransferase.

A 31-year-old man was referred for the evaluation of atypical Charcot-Marie-Tooth–like polyneuropathy. The family history was unremarkable except for a maculopathy in the patient's brother. Pregnancy, delivery, and the perinatal period were normal. A congenital cataract was detected and treated at 3 months of age. He walked at age 16 months. The first walking difficulties appeared at age 8 years and slowly increased thereafter, but the patient could still walk without help. Progressive disability was noticed in the upper limbs from age 26 years onward, making writing and buttoning increasingly difficult. Clinical examination at age 30 years showed distal amyotrophy in the upper and lower limbs, with length-dependent symmetrical sensorimotor deficits. Motor deficit was severe distally in the lower limbs (Medical Research Council grade [of a possible 5]: 1 for the tibialis anterior, 0 for the extensor hallucis longus, 3 for the fibularis longus, and 3 for the triceps surae), moderate in hand muscles (grade 3 for the palmar interossei and 4 for the abductor pollicis brevis), and absent proximally (global Medical Research Council score of 86 of a possible 100). Superficial sensory loss was noted up to the middle of the thighs and elbows, and deep sensory impairment was noted up to the knees and wrists. Ankle and wrist tendon reflexes were absent. Head circumference was 54 cm (third percentile). He had an asymptomatic multidirectional nystagmus. His gait was slightly ataxic due to a cerebellar syndrome. The Overall Neuropathy Limitations Scale score, measuring functional impairment, was 5 of a possible 12. The Mini-Mental State Examination score was 20 (of a possible 30), and the Frontal Assessment Battery score was 11 (of a possible 18).

Nerve conduction studies showed severe axonal sensorimotor polyneuropathy compatible with Charcot-Marie-Tooth disease type 2: absence of sensory nerve action potentials in the 4 limbs, absence of compound motor action potentials in the lower limbs, and reduced compound motor action potentials in the upper limbs, with preserved conduction velocities (Table). Needle electromyography revealed a 4-limb chronic neurogenic pattern with active denervation signs. Brain magnetic resonance imaging showed nonspecific T2-weighted hyperintensities, and findings from magnetic resonance spectroscopy were normal. Acquired causes of axonal polyneuropathies were excluded. No mutations were found in the genes most commonly responsible for Charcot-Marie-Tooth disease, including PMP22, P0, MFN2, GDAP1, and GJB1 (connexin 32). Because of congenital cataracts and mild mental retardation, a metabolic workup was performed to search for inborn errors of metabolism causing peripheral neuropathies.5 Amino acid chromatography showed low serine levels in plasma (0.35 mg/dL [reference range, 0.66-2.26 mg/dL] [to convert to micromoles per liter, multiply by 95.156]) and in cerebrospinal fluid (CSF) (0.14 mg/dL [reference range, 0.21-0.43 mg/dL]). Glycine levels were also decreased in plasma (0.70 mg/dL [reference range, 0.94-2.62 mg/dL] [to convert to micromoles per liter, multiply by 133.2]) but normal in CSF (0.05 mg/dL [reference range, 0.02-0.08 mg/dL]). Standard CSF investigations showed normal cellularity but a high protein concentration (0.11 g/dL [to convert to grams per liter, multiply by 10]).

Table Graphic Jump LocationTable. Motor Nerve Conduction Study Findings Before Treatment

Sequencing of the PGDH gene6 revealed 2 compound heterozygous mutations: a novel mutation (c.1471C>T), predicted to change arginine at position 491 to tryptophan, and an already reported one (c.1273G>A),7 predicted to change valine at position 425 to methionine (Figure 2). Mutation analysis in the patient's parents confirmed that these mutations were inherited in an autosomal recessive manner. The newly described mutation was not found in 105 control participants, as determined by allele-specific polymerase chain reaction.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Mutational analysis of the patient and his parents. Two heterozygous mutations, c.1273G>A (p.Val425Met) in exon 11 (inherited from the father) and c.1471C>T (p.Arg491Trp) in exon 12 (inherited from the mother), were found in the PGDH gene.

Serine treatment was introduced at 120 mg/kg/d in 3 divided doses. After 1 month, this treatment resulted in normalization of plasma serine values to 1.08 mg/dL and plasma glycine values to 1.61 mg/dL. The treatment was well tolerated, and the patient reported subjective improvement. The dose was then reduced to 80 mg/kg/d in 2 divided doses. Serine and glycine levels were maintained in the low-normal range in blood (serine: 0.90 mg/dL; glycine: 1.00 mg/dL), but serine levels were still slightly below the reference range in CSF (serine: 0.19 mg/dL; glycine: 0.05 mg/dL). After 3 months of treatment (120 mg/kg/d for 1 month and 80 mg/kg/d for 2 months), the patient felt better, could walk longer and faster, and was less clumsy. For example, walking time from work was reduced from 20 to 13 minutes, and he broke fewer plates at his workplace in a school canteen. This subjective improvement was also noticed by the family and was sustained during the following 9 months (last follow-up). Clinically, no objective significant changes were noted: the Medical Research Council and Overall Neuropathy Limitations Scale scores were the same, as were sensory examination findings. Only the Mini-Mental State Examination score seemed to have improved a bit, to 23 (of a possible 30). Findings from electromyographic analysis were unchanged after 1 and 4 months of treatment.

The 31-year-old patient described herein presented with an overall milder and phenotypically different form of serine synthesis defect secondary to 3-PGDH deficiency. He was a compound heterozygote for a known severe mutation and for a novel, and possibly milder, one.

This observation expands the clinical phenotype of 3-PGDH deficiency. Two autosomal recessive forms of PGDH deficiency have been described until now that differ mostly by their degree of severity. The most frequently reported infantile form is associated with congenital microcephaly, severe psychomotor retardation, and intractable seizures and is sometimes associated with cataracts, nystagmus, spastic tetraparesis, hypogonadism, and irritability.2,3,7 In those patients, brain magnetic resonance imaging shows hypomyelination or white matter attenuation.8 Recently, a milder form has been reported4 in 2 siblings with absence seizures of juvenile onset, mild developmental delay, and behavioral disturbances. No peripheral neuropathy was noticed in any of these patients; however, only a dozen patients have been described, from which it is difficult to delineate a full clinical spectrum.

Strong arguments support that the present patient's clinical symptoms, including neuropathy, are caused by a serine synthesis defect: (1) A case of serine deficiency associated with peripheral neuropathy has been previously reported9 in a 15-year-old girl who had decreased plasma and CSF serine levels. Oral treatment with serine, 400 mg/kg/d, was said to have improved her axonal polyneuropathy. Hyperactivity of serine hydroxymethyltransferase was suggested to be the cause in her case, but no molecular diagnosis was made.9 (2) The mild developmental delay and congenital cataracts observed in the present patient have been previously described in 3-PGDH deficiency.3,4 (3) Although we cannot exclude a placebo effect, sustained subjective improvement was reported by the patient and his family after treatment with oral serine and normalization of the blood serine concentration.

This case would then be one of the few pharmacologically treatable forms of Charcot-Marie-Tooth disease to be reported. A possible hereditary corticosteroid-responsive form was reported10 in 1982 but was never confirmed. Another potentially treatable form would be that of Charcot-Marie-Tooth disease type 2 caused by the TRPV4 mutation, in which treatment with calcium channel inhibitors could theoretically be beneficial.11 Furthermore, several inborn errors of metabolism potentially revealed by chronic peripheral neuropathy might be amenable to treatments, including cerebrotendinous xanthomatosis, pyruvate dehydrogenase deficiency, and Refsum disease.5

In the infantile form, treatment with serine, 500 to 700 mg/kg/d, and glycine, 200 to 300 mg/kg/d, resulted in lowered seizure frequency and increased white matter volume on magnetic resonance imaging but no or poor progression of psychomotor development.12 In the juvenile form, treatment with serine, 100 to 150 mg/kg/d, resulted in control of seizures and correction of behavioral abnormalities.4 In the present patient, an even lower dosage of 80 mg/kg/d resulted in normalization of plasma serine levels, but the CSF serine concentration remained slightly decreased, indicating that 120 mg/kg/d should be the best dosage. Although the patient reported subjective improvement of his condition, the treatment effect was not spectacular, with Medical Research Council and Overall Neuropathy Limitations Scale scores remaining stable. It is assumed that severe axonal loss resulting from a long-lasting untreated neuropathy is irreversible. Previous studies12,13 of patients with 3-PGDH deficiency disorder showed that clinical improvement was limited in patients treated after the onset of symptoms, whereas 1 patient treated before birth remained asymptomatic at age 5 years. This finding emphasizes the importance of early diagnosis and treatment in serine deficiency disorders, before irreversible neurologic damage occurs.

Considering the vast clinical spectrum of 3-PGDH deficiency, this disorder probably remains underdiagnosed. Since the condition is potentially treatable, plasma amino acid chromatography should be added to the list of investigations performed in patients with Charcot-Marie-Tooth–like polyneuropathy, especially if it is associated with psychomotor delay and congenital cataracts.

Correspondence: Frédéric Sedel, MD, PhD, Fédération des Maladies Du Système Nerveux, Hôpital de la Pitié-Salpêtrière, 47-83 Blvd de l’Hôpital, 75651 Paris CEDEX 13, France (frederic.sedel@psl.aphp.fr).

Accepted for Publication: August 11, 2011.

Published Online: March 5, 2012. doi:10.1001/archneurol.2011.1526

Author Contributions: All authors had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Study concept and design: Méneret, Wiame, Marelli, Van Schaftingen, and Sedel. Analysis and interpretation of data: Méneret, Wiame, Marelli, Lenglet, Van Schaftingen, and Sedel. Drafting of the manuscript: Méneret and Sedel. Critical revision of the manuscript for important intellectual content: Méneret, Wiame, Marelli, Lenglet, Van Schaftingen, and Sedel. Obtained funding: Wiame and Van Schaftingen. Study supervision: Wiame, Van Schaftingen, and Sedel.

Financial Disclosure: None reported.

Funding/Support: This study was supported by grants from the Fonds National de la Recherche Scientifique (Drs Wiame and Van Schaftingen).

Previous Presentation: This study was presented in part at the Society for the Study of Inborn Errors of Metabolism annual symposium; September 1, 2011; Geneva, Switzerland.

Yoshida K, Furuya S, Osuka S,  et al.  Targeted disruption of the mouse 3-phosphoglycerate dehydrogenase gene causes severe neurodevelopmental defects and results in embryonic lethality.  J Biol Chem. 2004;279(5):3573-3577
PubMed   |  Link to Article
Tabatabaie L, Klomp LW, Berger R, de Koning TJ. L-Serine synthesis in the central nervous system: a review on serine deficiency disorders.  Mol Genet Metab. 2010;99(3):256-262
PubMed   |  Link to Article
Jaeken J, Detheux M, Van Maldergem L, Foulon M, Carchon H, Van Schaftingen E. 3-Phosphoglycerate dehydrogenase deficiency: an inborn error of serine biosynthesis.  Arch Dis Child. 1996;74(6):542-545
PubMed   |  Link to Article
Tabatabaie L, Klomp LWJ, Rubio-Gozalbo ME,  et al.  Expanding the clinical spectrum of 3-phosphoglycerate dehydrogenase deficiency.  J Inherit Metab Dis. 2011;34(1):181-184
PubMed   |  Link to Article
Sedel F, Barnerias C, Dubourg O, Desguerres I, Lyon-Caen O, Saudubray JM. Peripheral neuropathy and inborn errors of metabolism in adults.  J Inherit Metab Dis. 2007;30(5):642-653
PubMed   |  Link to Article
Hart CE, Race V, Achouri Y,  et al.  Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway.  Am J Hum Genet. 2007;80(5):931-937
PubMed   |  Link to Article
Klomp LW, de Koning TJ, Malingré HE,  et al.  Molecular characterization of 3-phosphoglycerate dehydrogenase deficiency: a neurometabolic disorder associated with reduced L-serine biosynthesis.  Am J Hum Genet. 2000;67(6):1389-1399
PubMed   |  Link to Article
de Koning TJ, Jaeken J, Pineda M, Van Maldergem L, Poll-The BT, van der Knaap MS. Hypomyelination and reversible white matter attenuation in 3-phosphoglycerate dehydrogenase deficiency.  Neuropediatrics. 2000;31(6):287-292
PubMed   |  Link to Article
De Klerk JB, Huijmans JGM, Catsman-Berrevoets CE,  et al.  Disturbed biosynthesis of serine: a second phenotype with axonal polyneuropathy and ichthyosis. Abstracts of the annual meeting of the Erfelijke Stofwisselingsziekten Nederland; October 13, 1996; Masstricht, the Netherlands
Dyck PJ, Swanson CJ, Low PA, Bartleson JD, Lambert EH. Prednisone-responsive hereditary motor and sensory neuropathy.  Mayo Clin Proc. 1982;57(4):239-246
PubMed
Klein CJ, Shi Y, Fecto F,  et al.  TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies.  Neurology. 2011;76(10):887-894
PubMed   |  Link to Article
de Koning TJ. Treatment with amino acids in serine deficiency disorders.  J Inherit Metab Dis. 2006;29(2-3):347-351
PubMed   |  Link to Article
de Koning TJ, Klomp LWJ, van Oppen ACC,  et al.  Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency.  Lancet. 2004;364(9452):2221-2222
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Graphic Jump Location

Figure 1. The phosphorylated L-serine biosynthesis pathway. 3-PGDH indicates 3-phosphoglycerate dehydrogenase; PSAT, phosphoserine aminotransferase; PSPH, phosphoserine phosphatase; and SHMT, serine hydroxymethyltransferase.

Place holder to copy figure label and caption
Graphic Jump Location

Figure 2. Mutational analysis of the patient and his parents. Two heterozygous mutations, c.1273G>A (p.Val425Met) in exon 11 (inherited from the father) and c.1471C>T (p.Arg491Trp) in exon 12 (inherited from the mother), were found in the PGDH gene.

Tables

Table Graphic Jump LocationTable. Motor Nerve Conduction Study Findings Before Treatment

References

Yoshida K, Furuya S, Osuka S,  et al.  Targeted disruption of the mouse 3-phosphoglycerate dehydrogenase gene causes severe neurodevelopmental defects and results in embryonic lethality.  J Biol Chem. 2004;279(5):3573-3577
PubMed   |  Link to Article
Tabatabaie L, Klomp LW, Berger R, de Koning TJ. L-Serine synthesis in the central nervous system: a review on serine deficiency disorders.  Mol Genet Metab. 2010;99(3):256-262
PubMed   |  Link to Article
Jaeken J, Detheux M, Van Maldergem L, Foulon M, Carchon H, Van Schaftingen E. 3-Phosphoglycerate dehydrogenase deficiency: an inborn error of serine biosynthesis.  Arch Dis Child. 1996;74(6):542-545
PubMed   |  Link to Article
Tabatabaie L, Klomp LWJ, Rubio-Gozalbo ME,  et al.  Expanding the clinical spectrum of 3-phosphoglycerate dehydrogenase deficiency.  J Inherit Metab Dis. 2011;34(1):181-184
PubMed   |  Link to Article
Sedel F, Barnerias C, Dubourg O, Desguerres I, Lyon-Caen O, Saudubray JM. Peripheral neuropathy and inborn errors of metabolism in adults.  J Inherit Metab Dis. 2007;30(5):642-653
PubMed   |  Link to Article
Hart CE, Race V, Achouri Y,  et al.  Phosphoserine aminotransferase deficiency: a novel disorder of the serine biosynthesis pathway.  Am J Hum Genet. 2007;80(5):931-937
PubMed   |  Link to Article
Klomp LW, de Koning TJ, Malingré HE,  et al.  Molecular characterization of 3-phosphoglycerate dehydrogenase deficiency: a neurometabolic disorder associated with reduced L-serine biosynthesis.  Am J Hum Genet. 2000;67(6):1389-1399
PubMed   |  Link to Article
de Koning TJ, Jaeken J, Pineda M, Van Maldergem L, Poll-The BT, van der Knaap MS. Hypomyelination and reversible white matter attenuation in 3-phosphoglycerate dehydrogenase deficiency.  Neuropediatrics. 2000;31(6):287-292
PubMed   |  Link to Article
De Klerk JB, Huijmans JGM, Catsman-Berrevoets CE,  et al.  Disturbed biosynthesis of serine: a second phenotype with axonal polyneuropathy and ichthyosis. Abstracts of the annual meeting of the Erfelijke Stofwisselingsziekten Nederland; October 13, 1996; Masstricht, the Netherlands
Dyck PJ, Swanson CJ, Low PA, Bartleson JD, Lambert EH. Prednisone-responsive hereditary motor and sensory neuropathy.  Mayo Clin Proc. 1982;57(4):239-246
PubMed
Klein CJ, Shi Y, Fecto F,  et al.  TRPV4 mutations and cytotoxic hypercalcemia in axonal Charcot-Marie-Tooth neuropathies.  Neurology. 2011;76(10):887-894
PubMed   |  Link to Article
de Koning TJ. Treatment with amino acids in serine deficiency disorders.  J Inherit Metab Dis. 2006;29(2-3):347-351
PubMed   |  Link to Article
de Koning TJ, Klomp LWJ, van Oppen ACC,  et al.  Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency.  Lancet. 2004;364(9452):2221-2222
PubMed   |  Link to Article

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