Familial Hyperprolinemia, Cerebral Dysfunction and Renal Anomalies Occurring in a Family with Hereditary Nephropathy and Deafness

Schafer, Irwin A.; Scriver, Charles R.; Efron, Mary L.

doi:10.1056/nejm196207122670201

Cited by 135 publications

(45 citation statements)

References 27 publications

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“…The influence of metabolism on the transmembrane movement of proline in the human kidney raises some questions concerning the etiology of prolinuria in both the familial hyperprolinemic syndromes with known enzymatic defects [5,15,19,20] and the hyperprolinuria renal tubule syndromes [13,16,17,22]. The degree of prolinuria in the former syndromes may be related not only to an increased filtered load of proline but also to defects in the tubular metabolism of proline, resulting in impairment of tubular reabsorption of the filtered proline load.…”

Section: Discussionmentioning

confidence: 99%

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Metabolism and Uptake of L-Proline by Human Kidney Cortex

et al. 1973

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ExtractL-Proline transport and metabolism have been investigated in normal adult human kidney cortical slices. The uptake of proline from buffers containing both high (10 HIM) and low (0.23 HIM) 14 G-proline concentrations is intimately related to the extent of intracellular proline metabolism. The accumulation of radioactivity from both the 10 and 0.23 HIM proline media was against high radioactivity gradients, with distribution ratios of 18 and 3, respectively. Recovered proline from the intracellular fluid (IGF) accounted for less than 12% of the intracellular radioactivity in the tissue extracts. Glutamic acid accounted for greater than 75% of the intracellular form of the soluble radioactivity in tissue extracts. Total oxidation to 14 CC>2 from both proline concentrations accounted for more than 50% of the total proline taken up by the slices.Kinetic analysis of the entry process suggested the existence of two saturable systems : one operative at low or physiologic proline concentrations (apparent K m 2 HIM) with a low capacity (F max 40 juM-ml ICF~x-30 min" 1 ) and shared with neutral amino acids, and a second with an affinity to 10-fold less (apparent K m 17 HIM) with a high capacity (F raax 160 /uM-ml ICF~1-30 min" 1 ) and unshared by the neutral amino acids. Separation of the influence of metabolism from the analysis of the transport systems by the use of proline analogues showed that thioproline inhibited proline uptake by 80%, primarily by reducing the conversion of proline to glutamic acid, whereas 3,4-dehydroproline did not affect the conversion of proline to glutamic acid but principally appeared to alter the affinity of the transport system for proline. SpeculationThese studies suggest that changes in the rate of proline metabolism in the human kidney may alter the rate of tubular reabsorption, thus controlling renal proline excretion. It is possible that renal iminoglycinuric syndromes may not only be secondary to membrane transport disorders but may result from localized metabolic defects in the tubule cells. Introductionent during the early postnatal period in humans and gradually diminishes by the 6th month of life as the In humans, excessive excretion of the iminoacids-pronet tubular reabsorption of glycine and the iminoacids line and hydroxyproline-and glycine is found in cerincreases. Delayed postnatal maturation of the imitain clinical situations, either as an isolated benign noacid and glycine transport system in the renal tuaminoaciduria or associated with other systemic findbule appears to be responsible for this benign finding ings. Hyperexcretion of iminoacids and glycine is pres- [3,25].

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Section: Discussionmentioning

confidence: 99%

“…In contrast to these membrane transport defects, a familial hyperprolinemia syndrome which may be associated with mental retardation and renal malformations has been described [5,15,19,20]. Deficiency of either proline oxidase or A'-pyrroline-5-carboxylic acid dehydrogenase results in hyperprolinemia.…”

Section: Introductionmentioning

confidence: 99%

Metabolism and Uptake of L-Proline by Human Kidney Cortex

et al. 1973

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“…Several disorders in proline metabolism have been identified, such as deficiency of POX or Hyperprolinemia type I (HPI) and deficiency of the activity of D1-P5C dehydrogenase or Hyperprolinemia type II (HPII). Both rare diseases, inherited as autosomal recessive disorders and characterized biochemically by high proline levels [4][5][6]. Although the neuropsychiatric phenotype has been primarily associated with HPII [6,7], a growing number of patients with these features, in particular schizophrenia, have been documented for HPI [8].…”

Section: Introductionmentioning

confidence: 99%

Hyperprolinemia as a clue in the diagnosis of a patient with psychiatric manifestations

Duarte

Afonso

Moreira

et al. 2017

Brain and Development

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Lately, microdeletions of the 22q region, responsible for DiGeorge syndrome or velocardiofacial syndrome, have been increasingly related to neuropsychiatric disorders including schizophrenia and bipolar disorder. These manifestations seem to be related to certain genes located in the hemideleted region such as the proline dehydrogenase (PRODH) and the catechol-o-methyltransferase (COMT) genes.We describe a teenager who started his adolescent psychiatric care presenting cognitive impairment, irritable mood and aggressive behaviour with schizophrenia-like symptoms that scored 153 in the Positive and Negative Symptoms Scale (PANSS) assessment.Worsening of symptoms when the patient was treated with valproic acid, and plasma aminoacids showing an increase in alanine and proline, suggested a mitochondrial involvement of the proline metabolic pathway. Mild dysmorphic features also suggested a possible 22q11 deletion syndrome that was confirmed. A mutation for Hyperprolinemia type I was also detected.Knowledge of the correct diagnosis was crucial for an adequate treatment.

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“…And in the 1980s, the conversion of P5C to proline was recognized to regulate redox homeostasis as mentioned above [8,14,15]. A variety of evidence has shown the inborn errors of the proline metabolic pathway in several human genetic diseases and their potential roles [11,16], such as familial hyperprolinemias [11,17], mutations of PRODH/POX in neuropsychiatric diseases [18,19], mutations of PYCR1 in cutis laxa [20], mutations of P5CS in hyperammonemia [21,22], and so on. During the last decade, our understanding of the roles of proline metabolism as represented by the regulation and functions of PRODH/POX in tumorigenesis and tumor progression has made significant advances, which will be main focus in this chapter.…”

Section: Introductionmentioning

confidence: 99%