Proline synthesis disorders
The third group in the amino acids synthesis disorders are the defects in the synthesis of the amino acid L-proline. Whereas defects in the synthesis of L-serine and L-glutamine lead to serious seizure disorders; developmental delay and connective tissue disease are the clinical hallmarks of the synthesis defects in L-proline.
In these disorders the non-neurological symptoms should alert the clinician to the possibilities of a proline synthesis disorder. This enzymatic defect results in a combined deficiency of L-proline, L-ornithine, L-citrulline, and L-arginine and causes a slowly progressive neurodegenerative disorder of the central and peripheral nervous system, combined with cataracts and extensive connective tissue involvement (Baumgartner et al., 2000, 2005).
A limited number of families have been reported with this defect in the synthesis of proline and ornithine. The first family was published by Baumgartner et al. with a rather complex phenotype. In consanguineous this family the molecular defect resulted in a combined deficiency of the amino acids proline, ornithine, citrulline and arginine, in combination with an elevated ammonia in the fasted state. In infancy, the patients presented with feeding difficulties, failure to thrive, gastroesophageal reflux, and vomiting. In addition to this, they were severely hypotonic and demonstrated extensive jointlaxity. One patient was reported to have had seizures in the neonatal period.
During childhood, the children developed cataracts and demonstrated dysmorphic features together with long fingers and toes and a short neck. Psychomotor development was very slow, with walking independently at 4 years and talking at 5 years. From childhood to adolescence both sibs showed a progressive loss of mental and motor skills, displayed abnormal behavior, dystonia, wasting of muscle mass, and bilateral pyramidal symptoms combined with a neuropathy of predominantly the axonal type. Patients lost ambulation and became wheelchair-bound in their teens. At adult age they had small stature and low IQs (50). In only one patient an MRI was performed showing mild white matter atrophy.
Whereas the first family reported by Baumgartner (mild) mental retardation was most prominent, other patients reported had serious developmental delay and neonatal seizures and a movement disorder. One patient died in infancy (Bicknell et al., 2008, Skidmore et al., 2011).
In a recent report additional features were tortuosity of brain vessels and lowered brain creatine concentration demonstrated by MRS. The latter finding was important, because this opened up possibilities for treatment see below (Martinelli et al., 2012).
MRI abnormalities were reported by Bicknell et al. (2008) and Martinelli et al. (2012) and consisted of hypoyelination, cortical atrophy, hypoplastic corpus callosum and tortuosity of brain vessels.
Both patients were treated with oral L-ornithine, one from the age of 5 years and in the other treatment was started at 12 years. Disappointingly, this treatment with L-ornithine had no effect on the symptoms or on disease progression.
However, in a recent paper Martinelli et al. (2012) a single patient was treated with L-arginine (150 mg/kg/day) because of creatine deficiency in brain demonstrated by MRS. Supplementation with L-arginine resulted in biochemical improvement (in particular fasting ammonia, proline and ornithine concentrations, improvement of developmental delay and normalisation of brain creatine concentrations on MRS. According to the authors the (secondary) deficiency of brain creatine may be an important factor in de neurological symptoms in the neurological symptoms observed in this disorder.
Amino acid analysis in plasma showed a combined deficiency of proline, arginine, citrulline, and ornithine. This is a very unusual combination of lowered plasma amino acids. Low values of arginine, citrulline, and ornithine are observed in urea cycle defects or its related disorders, but the combination with low proline is only observed in this defect. Routine biochemical diagnostic tests only showed mildly elevated ammonia which, in contrast to all other metabolic disorders, went down after meals. The diagnosis is confirmed by mutation analysis of the P5CS gene (Baumgartner et al., 2000). Unfortunately, the biochemical abnormalities need not to be present in every patient, which makes it very difficult to rely solely on biochemical diagnosis. Upon a clinical suspicion mutation analysis of the ALDH18A1 gene is mandatory to make this diagnosis.
Pyrroline-5carboxylate reductase 1 deficiency
The second disorder in proline synthesis pyrroline-5carboxylate reductase 1 deficiency (PYCR1 deficiency) shows many overlapping symptoms with the other proline disorder. Patients have primarily a connective tissue disorder loose inelastic wrinkly skin, joint laxicity, progeroid features and developmental delay (Reversade et al., 2009; Guernsey et al., 2009), similar to what is observed P5CS deficiency. In contrast, plasma concentrations of amino acids are normal and low levels of proline or other amino acids have not been reported.
This disorder was first reported by Reversade et al. in 2009 as a cutis laxa phenotype with progeroid features with some patients also having mental retardation. In a recent report additional features such as intrauterine growth retardation, hipdysplasia, dysmorfic features (triangular face, loss of adipose tissue and thin pointed nose), short stature, wrinkling of the skin over dorsum of hands and feet, joint laxity were documented (Kretz et al., 2011). In the latter studies it was confirmed that mental retardation is not present in all patients.
Therefore the non-neurological symptoms are most important guiding the diagnostic steps that should be taken.
Given the fact that there are no biochemical abnormalities documented in this disorder mutation analysis of the PYCR1 gene should be done in case of a clinical suspicion. At present there are no reports about therapeutic interventions in this disorder.
|Molar mass||443.414 g/mol|
Except where otherwise noted, data are given for materials in their standard state (at 25 °C [77 °F], 100 kPa).
|Y verify (what is YN ?)|
Dihydrofolic acid (conjugate base dihydrofolate) (DHF) is a folic acid (vitamin B9) derivative which is converted to tetrahydrofolic acid by dihydrofolate reductase. Since tetrahydrofolate is needed to make both purines and pyrimidines, which are building blocks of DNA and RNA, dihydrofolate reductase is targeted by various drugs to prevent nucleic acid synthesis.
Interactive pathway map
Click on genes, proteins and metabolites below to link to respective articles.[§ 1]