Smith-Magenis syndrome (SMS) and Potocki-Lupski syndrome (PTLS) are reciprocal contiguous gene syndromes within the well-characterized 17p11.2 region. Approximately 3.6 Mb microduplication of 17p11.2, known as PTLS, represents the mechanistically predicted homologous recombination reciprocal of the SMS microdeletion, both resulting in multiple congenital anomalies. Mouse model studies have revealed that the retinoic acid-inducible 1 gene (RAI1) within the SMS and PTLS critical genomic interval is the dosage-sensitive gene responsible for the major phenotypic features in these disorders. Even though PTLS and SMS share the same genomic region, clinical manifestations and behavioral issues are distinct and in fact some mirror traits may be on opposite ends of a given phenotypic spectrum. We describe the neurobehavioral phenotypes of SMS and PTLS patients during different life phases as well as clinical guidelines for diagnosis and a multidisciplinary approach once diagnosis is confirmed by array comparative genomic hybridization or RAI1 gene sequencing. The main goal is to increase awareness of these rare disorders because an earlier diagnosis will lead to more timely developmental intervention and medical management which will improve clinical outcome.
Nonketotic hyperglycinemia (NKH) is caused by deficient glycine cleavage enzyme activity and characterized by elevated brain glycine. Metabolism of glycine is connected enzymatically to serine through serine hydroxymethyltransferase and shares transporters with serine and threonine. We aimed to evaluate changes in serine and threonine in NKH patients, and relate this to clinical outcome severity. Age‐related reference values were developed for cerebrospinal fluid (CSF) serine and threonine from 274 controls, and in a cross‐sectional study compared to 61 genetically proven NKH patients, categorized according to outcome. CSF d‐serine and l‐serine levels were stereoselectively determined in seven NKH patients and compared to 29 age‐matched controls. In addition to elevated CSF glycine, NKH patients had significantly decreased levels of CSF serine and increased levels of CSF threonine, even after age‐adjustment. The CSF serine/threonine ratio discriminated between NKH patients and controls. The CSF glycine/serine aided in discrimination between severe and attenuated neonates with NKH. Over all ages, the CSF glycine, serine and threonine had moderate to fair correlation with outcome classes. After age‐adjustment, only the CSF glycine level provided good discrimination between outcome classes. In untreated patients, d‐serine was more reduced than l‐serine, with a decreased d/l‐serine ratio, indicating a specific impact on d‐serine metabolism. We conclude that in NKH the elevation of glycine is accompanied by changes in l‐serine, d‐serine and threonine, likely reflecting a perturbation of the serine shuttle and metabolism, and of one‐carbon metabolism. This provides additional guidance on diagnosis and prognosis, and opens new therapeutic avenues to be explored.
Potocki-Lupski Syndrome (PTLS, MIM 610883), or duplication of chromosome 17p11.2, is a clinically recognizable condition characterized by infantile hypotonia, failure to thrive, developmental delay, intellectual disability, and congenital anomalies. Short stature, classified as greater than two standard deviations below the mean, has not previously been considered a major feature of PTLS.Retrospective chart review on a cohort of 37 individuals with PTLS was performed to investigate the etiology of short stature. Relevant data included anthropometric measurements, insulin growth factor-1 (IGF-1), insulin-like growth factor binding protein 3 (IGFBP-3), growth hormone (GH) stimulation testing, blood glucose levels, brain MRI, and bone age.
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