25 Disorders of and

Jaak Jaeken

25.1 Inborn Errors of Proline Metabolism – 317 25.1.1 Deficiency ( Type I) – 317 25.1.2 ∆1-Pyrroline 5-Carboxylate Deficiency (Hyperprolinemia Type II) – 317

25.2 Inborn Errors of Serine Metabolism – 318 25.2.1 3-Phosphoglycerate Dehydrogenase Deficiency – 318 25.2.2 Deficiency – 318 25.2.3 Serine Deficiency with Ichthyosis and Polyneuropathy – 318

References – 319 316 Chapter 25 · Disorders of Proline and Serine Metabolism

Proline and Serine Metabolism Proline and serine are non-essential amino acids. Un- Serine also has important functions besides its role like all other amino acids (except ), pro- in synthesis. It is a precursor of a number of line has no primary amino group (it is termed an imino compounds (partly illustrated in . Fig. 25.2), including acid) and uses, therefore, a specific system of d-serine, , , serine , sphin- for its metabolism (. Fig. 25.1). '1-Pyrroline 5-carbo- gomyelins, and cerebrosides. Moreover, it is a major xylate (P5-C) is both the immediate precursor and the source of N5,N10-methylene-tetrahydrofolate (THF) degradation product of proline. The P5-C/proline cycle and of other one-carbon donors that are required for IV transfers reducing/oxidizing potential between cellular the synthesis of and thymidine. Serine is syn- organelles. Due to its ring, proline (together thesized de novo from a glycolytic intermediate, 3-phos- with hydroxyproline) contributes to the structural phoglycerate and can also be synthesized from glycine stability of , particularly , with its high by reversal of the reaction catalyzed by serine hydro- proline and hydroxyproline content. xymethyltransferase, which thereby converts N5,N10- methylene-THF into THF (7 also Fig. 24.1).

. Fig. 25.1. Proline metabolism. Shaded area represents mito- (deficient in hyperprolinemia type 2); 3, P5-C synthase; 4, P5-C re- chondrial membrane. Cit, ; Glu, ; Orn, ; ductase; 5, non-enzymatic reaction; 6, ornithine aminotransferase Pro, proline; P5-C, '1-pyrroline 5-carboxylate. 1, Proline oxidase (deficient in gyrate atrophy). Bars across arrows indicate defects (deficient in hyperprolinemia type 1); 2, P5-C dehydrogenase of proline metabolism

. Fig. 25.2. Pathway of de novo serine synthesis. P, phosphate; 5, . Glycine is synthesized from serine, but also 1, 3-phosphoglycerate dehydrogenase; 2, 3-phosphohydroxy- from other sources. Bars across arrows indicate the known defects pyruvate transaminase; 3, 3-phosphoserine phosphatase; in serine synthesis 4, serine hydroxymethyltransferase (utilizes tetrahydrofolate); 317 25 25.1 · Inborn Errors of Proline Metabolism

Genetics Three disorders of proline metabolism are known: two The mode of inheritance is autosomal recessive. PRODH, in its catabolism (hyperprolinemia type I due to proline the encoding proline oxidase, maps to 22q11, in the oxidase deficiency and hyperprolinemia type II due to region deleted in the velocardiofacial syndrome/DiGeorge '1-pyrroline 5-carboxylate dehydrogenase deficiency) syndrome. At least 16 missense mutations have been iden- and one in its synthesis ('1-pyrroline 5-carboxylate syn- tified [4, 5]. thase deficiency). Hyperprolinemia type I is mostly con- sidered a non-disease, while hyperprolinemia type II Diagnostic Tests seems to be associated with a disposition to recurrent The diagnosis is made by analysis. Direct en- seizures. The deficiency of the proline-synthesizing zyme assay is not possible, since the is not present enzyme, '1-pyrroline 5-carboxylate synthase, which in leukocytes or skin fibroblasts. Mutation analysis is thus also intervenes in ornithine synthesis, is described in necessary to confirm the diagnosis [4]. 7 Chap. 22. Three disorders of serine metabolism are known. Treatment and Prognosis Two are in its : namely, 3-phosphoglycerate Since the prognosis is generally excellent, dietary treatment dehydrogenase deficiency and phosphoserine phos- is not indicated. phatase deficiency. Patients with 3-phosphoglycerate dehydrogenase deficiency are affected with congenital 1 microcephaly, psychomotor retardation and intractable 25.1.2 ∆ -Pyrroline 5-Carboxylate seizures and partially respond to L-serine or L-serine Dehydrogenase Deficiency and glycine. One patient with an association of Williams (Hyperprolinemia Type II) syndrome and phosphoserine phosphatase deficiency has been reported. Another, unexplained serine dis- Clinical Presentation order has been reported in a patient with decreased This is a relatively benign disorder, though a disposition to serine in body fluids, ichthyosis and polyneuropathy recurrent seizures is highly likely [2]. but no central nervous system manifestations. There was a spectacular response to L-serine. Metabolic Derangement Hyperprolinemia type II is caused by a deficiency of P5-C dehydrogenase, a mitochondrial inner-membrane enzyme, which intervenes in the conversion of proline into gluta- mate (. Fig. 25.1, enzyme 2). Hence, in hyperprolinemia 25.1 Inborn Errors of Proline type II, there are increased levels of proline in plasma Metabolism (usually exceeding 2000 µM; normal range 100–450 µM), urine and CSF, as well as of P5-C. Heterozygotes do not 25.1.1 Proline Oxidase Deficiency have hyperprolinemia. Evidence has been presented that (Hyperprolinemia Type I) the accumulating P5-C is a B6 antagonist (due to adduct formation) and that the seizures in this dis- Clinical Presentation order may be due at least in part to inactiva- Hyperprolinemia type I is a very rare disorder, generally tion [6, 6a]. considered a benign trait but recent work suggests that it may be associated with a subset of schizophrenic patients Genetics [1–4]. This is an autosomal-recessive disease. The gene ALDH4A1 maps to 1p36. Mutations have recently been reported in Metabolic Derangement four patients (two frame-shift mutations and two missense Hyperprolinemia type I is caused by a deficiency of proline mutations) [7]. oxidase (a mitochondrial inner-membrane enzyme), which catalyses the conversion of proline into P5-C (. Fig. 25.1, Diagnostic Tests enzyme 1). Hence, in hyperprolinemia type I, there are The accumulation of P5-C in physiological fluids differen- increased levels of proline in plasma (usually not above tiates type-II and type-I hyperprolinemia. This compound 2000 µM; normal range 100–450 µM), urine and cerebro- can be qualitatively identified by its reactivity with ortho- spinal fluid (CSF). Hyperprolinemia (as high as 1000 µM) aminobenzaldehyde and can be quantitatively measured by is also observed as a secondary phenomenon in hyper- several specific assays [2]. P5-C-dehydrogenase activity can lactatemia, possibly due to inhibition of proline oxidase be measured in skin fibroblasts and leukocytes. by lactic acid. Remarkably, and in contrast with hyperpro- linemia type II, heterozygotes have hyperprolinemia. 318 Chapter 25 · Disorders of Proline and Serine Metabolism

Treatment and Prognosis Diagnostic Tests The benign character of the disorder does not justify dietary The diagnosis should be suspected in patients with ence- treatment (which, in any case, would be very difficult). Sei- phalopathy comprising congenital microcephaly. Plasma zures are B6 responsive. amino acids must be measured in the fasting state (range in patients: 28–64 µM; normal range: 70–187 µM), since serine and glycine levels can be normal after feeding. In 25.2 Inborn Errors of Serine CSF, serine levels are always decreased (6–8 µM; control Metabolism range 35–80 µM), as are glycine levels, but to a lesser extent. The diagnosis is confirmed by finding a deficient activity of IV 25.2.1 3-Phosphoglycerate Dehydro- 3-phosphoglycerate dehydrogenase in fibroblasts (reported genase Deficiency residual activities from 6–22%).

Clinical Presentation Treatment and Prognosis At least nine patients belonging to four families with this Treatment with L-serine has a beneficial effect on the con- disease (first reported in 1996) are known [8, 9]. They pre- vulsions, spasticity, feeding and behaviour of these patients. sented at birth with microcephaly and developed pro- Oral L-serine treatment (up to 600 mg/kg/day in six divided nounced psychomotor retardation, severe spastic tetra- doses) corrected the biochemical abnormalities in all re- plegia, nystagmus, and intractable seizures (including hyps- ported patients and abolished the convulsions in most pa- arrythmia). tients, even in those in whom many anti-epileptic treat- In addition, one patient showed congenital bilateral ment regimens had failed previously. During treatment cataract, two siblings growth retardation and hypogona- with L-serine, a marked increase in the white matter volume dism, and two other siblings megaloblastic anemia. Mag- was observed, and in some patients a progression of mye- netic resonance imaging of the brain revealed cortical and lination [12]. In two patients, convulsions stopped only af- subcortical hypotrophy and evidence of disturbed myelina- ter adding glycine (200 mg/kg/day). tion. In a girl diagnosed prenatally, because of decelerating head growth, L-serine was given to the mother at 190 mg/ Metabolic Derangement kg/day in 3 divided doses from the 27th week of gestation. The deficiency of 3-phosphoglycerate dehydrogenase, the This normalized fetal head growth and with subsequent first step of serine biosynthesis (. Fig. 25.2, enzyme 1), postnatal therapy the girl showed normal psychomotor causes decreased concentrations of serine and, to a lesser development at the age of 3 years [11]. extent, of glycine in CSF and in fasting plasma. Serine thus becomes an in these patients. A sig- nificant accumulation of the substrate, 3-phosphogly cerate, 25.2.2 Phosphoserine Phosphatase is unlikely since it is an intermediate of the glycolytic path- Deficiency way. Therefore, the deficiency of brain serine seems to be the main determinant of the disease. Serine plays a major Decreased serine levels were found in plasma (53–80 µM; role in the synthesis of important brain and myelin con- normal range 70–187 µM) and CSF (18 µM; control range stituents, such as proteins, glycine, cysteine, serine phos- 27–57 µM) of one patient with Williams syndrome [13]. pholipids, and cerebrosides. Phosphoserine phosphatase activity in lymphoblasts and In the two patients with megaloblastic anemia, de- fibroblasts amounted to about 25% of normal (. Fig. 25.2, creased methyltetrahydrofolate was found in CSF. This can enzyme 3). Oral serine normalized plasma and CSF levels be explained by the fact that serine is converted into gly- of this amino acid and seemed to have some beneficial cine by a reaction that forms methylenetetrahydrofolate clinical effect. The gene was mapped to 7p11, and the pa- (. Fig. 24.1), which is further reduced to methyltetrahydro- tient was found to be a compound heterozygote for two (7 Chap. 28). missense mutations, excluding a link with Williams syn- drome [14]. Genetics This is an autosomal-recessive disease. The gene for 3-phos- phoglycerate dehydrogenase has been mapped to 1q12. 25.2.3 Serine Deficiency with Ichthyosis Two missense mutations have been identified [10]. Prenatal and Polyneuropathy diagnosis is only possible by mutation analysis as there is a lack of data on enzyme activity in chorionic villi and A remarkable new serine-deficiency syndrome has been amniocytes [11]. discovered by De Klerk et al. [15] in a 15-year-old girl. She had ichthyosis from the first year of life, growth retardation from the age of 6 years and presented at the age of 14 years 319 25 References

with walking difficulties and areflexia, symptoms of an axonal polyneuropathy. Psychomotor development and magnetic resonance imaging of the brain were normal. Fasting plasma and CSF serine levels were decreased but the CSF glycine level slightly increased. Oral ingestion of serine (400 mg/kg/day) cured the skin lesions and the polyneuropathy. It is hypothesized that this patient exhibits an increased conversion of serine into glycine, possibly due to hyper activity of serine hydroxymethyltransferase (. Fig. 25.2, enzyme 4).

References

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6a. Clayton PT (2006) B6-Responsive disorders: a model of vitamin de- pendency. J Inherit Metab Dis 29:317-326 7. Geraghty MT, Vaughn D, Nicholson AJ et al (1998) Mutations in the delta 1-pyrroline 5-carboxylate dehydrogenase gene cause type II hyperprolinemia. Hum Mol Genet 7:1411-1415 8. Jaeken J, Detheux M, Van Maldergem L et al (1996) 3-Phospho- glycerate dehydrogenase deficiency: an inborn error of serine bio- synthesis. Arch Dis Child 74:542-545 9. de Koning TJ, Klomp LWJ (2004) Serine-deficiency syndromes. Curr Opin Neurol 17:197-204 10. Klomp LW, de Koning TJ, Malingre HE et al (2000) Molecular charac- terization of 3-phosphoglycerate dehydrogenase deficiency – a neurometabolic disorder associated with reduced L-serine bio- synthesis. Am J Hum Genet 67:1389-1399 11. de Koning TJ, Klomp LW, van Oppen AC et al (2004) Prenatal and early postnatal treatment in 3-phosphoglycerate-dehydrogenase deficiency. Lancet 364:2221-2222 12. de Koning TJ, Jaeken J, Pineda M et al (2000) Hypomyelination and reversible white matter attenuation in 3-phosphoglycerate dehy- drogenase deficiency. Neuropediatrics 31:287-292 13. Jaeken J, Detheux M, Fryns J-P et al (1997) Phosphoserine phos- phatase deficiency in a patient with Williams syndrome. J Med Genet 34:594-596 14. Veiga-da-Cunha M, Collet JF, Prieur B et al (2004) Mutations re- sponsible for 3-phosphoserine phosphatase deficiency. Eur J Hum Genet 12:163-166 15. De Klerk JB, Huijmans JGM, Catsman-Berrevoets CE et al (1996) Dis- turbed biosynthesis of serine; a second phenotype with axonal poly- neuropathy and ichthyosis. Abstracts of the annual meeting of the Erfelijke Stofwisselingsziekten Nederland, Maastricht, 13–15 Oct 1996