Pyrroline-5-Carboxylate Reductase 2 Deficiency: A New Case and Review of the Literature

Pyrroline-5-carboxylate reductase 2 (EC 1.5.1.2) is involved in the endogenous proline synthesis from glutamate and pyrroline-5-carboxylate. 1,2 Its deficiency (MIM#616420) is caused by biallelic variants in PYCR2.Proline is an important amino acid for central nervous system and connective tissues. 2 Less than 30 patients have been reported in the literature. [3][4]4][5][6] The clinical features include global developmental delay, acquired microcephaly, movement disorder, seizures, and failure to thrive. [3][4]][5][6] We report a new patient with a known pathogenic homozygous PYCR2 variant who presented with early infantile onset severe global developmental delay, acquired microcephaly, failure to thrive, and delayed myelination in brain magnetic resonance imaging (MRI).Additionally, we summarized all patients published in the literature for their phenotype and genotype in this case report.This 2-year 2-month-old girl was born to healthy consanguineous Egyptian parents.The pregnancy was remarkable for maternal hypothyroidism and thyroid hormone treatment.She was delivered by an elective caesarian section at 37 weeks of gestation.Birth weight was at the 3rd percentile.Her apgars were 9 and 10 at 1 and 5 minutes, respectively.She was formula-fed due to lack of breast milk production.There was persistent vomiting and failure to thrive from the first few months of life.She was started on oral ranitidine at 4 months of age and vomiting was improved, but not failure to thrive.Developmental delay was noted from the first few months of age.She had her first generalized tonic seizure lasting 1 minute at the age of 7 months.Her electroencephalography (EEG) showed intermittent diffuse 2-3 Hz delta slowing indicating cortical encephalopathy with no epileptogenic discharges at the age of 8 months.She underwent video EEG recording, which showed four brief myoclonic jerks during drowsiness and wakefulness with generalized 2.5-3 Hz spike-and polyspike-and-wave complexes.There was intermittent sharply contoured slow-wave activity over bilateral temporal head region during sleep.She was started on levetiracetam.At the age of 18 months, she was attempting to reach objects, roll from prone to supine, and was babbling.She did not achieve unsupported sitting or acquired any words at the age of 26 months.Her weight, height, and head circumference were below the 3rd percentile.She had full eyebrows, upslanting palpebral fissures, long eyelashes, bulbous nasal tip, absent antihelix bilaterally and plagiocephaly.She had central hypotonia.Muscle stretch reflexes were +2 and symmetrical.Chromosomal microarray, ammonia, lactate, acylcarnitine profile, plasma amino acids, total and free carnitine, total homocysteine, very long chain fatty acids, transferrin isoelectric focusing, urine organic acids, urine oligosaccharides and urine Hmz c.355C>T (p.Arg119Cys) in PYCR2 3 b /9.4 3 GDD, nonambulatory, dysmorphic features, microcephaly, FTT, muscle wasting Hypomyelination, thin corpus callosum, thin brain stem Hmz c.751C>T (p.Arg251Cys) in PYCR2 4 b /7.6 3 GDD, nonambulatory, dysmorphic features, microcephaly, FTT, muscle wasting Hypomyelination, thin corpus callosum, thin brain stem Hmz c.751C>T (p.Arg251Cys) in PYCR2 5 c /6 5 GDD, seizures, nonambulatory, dysmorphic features, microcephaly, FTT, muscle wasting, spasticity Demyelination, thin corpus callosum Hmz c.28C>T (p.Glu10*) in PYCR2 6 c /2.1 5 GDD, seizures, nonambulatory, dysmorphic features, microcephaly, FTT, spasticity Delayed myelination, thin corpus callosum Hmz c.28C>T (p.Glu10*) in PYCR2 7/2.4 5 GDD, nonambulatory, dysmorphic features, microcephaly, FTT Delayed myelination, agenesis of corpus callosum Hmz c.796C>T h (p.Arg266*) in PYCR2 8 d /16.8 5 GDD, seizures, nonambulatory, dysmorphic features, microcephaly, FTT, spasticity Cerebral atrophy Hmz c.577G>A (p.Val193Met) in PYCR2 9 d /12.7 5 GDD, FTT, microcephaly, spasticity NA Hmz c.577G>A (p.Val193Met) in PYCR2 10 e /5 died 4 GDD, nonambulatory, hyperkinetic movements, dysmorphic features, microcephaly, FTT, muscle wasting, spasticity Temporal atrophy Hmz c.796G>A h (p.Arg266*) in PYCR2 11 e /NA 4 GDD, nonambulatory,

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