Genotype and phenotype in 12 additional individuals with SATB2-associated syndrome.

SATB2-associated syndrome (SAS) is a multisystemic disorder caused by alterations of the SATB2 gene. We describe the phenotype and genotype of 12 individuals with 10 unique (de novo in 11 of 11 tested) pathogenic variants (1 splice site, 5 frameshift, 3 nonsense, and 2 missense) in SATB2 and review all cases reported in the published literature caused by point alterations thus far. In the cohort here described, developmental delay (DD) with severe speech compromise, facial dysmorphism, and dental anomalies were present in all cases. We also present the third case of tibial bowing in an individual who, just as in the previous 2 individuals in the literature, also had a truncating pathogenic variant of SATB2. We explore early genotype-phenotype correlations and reaffirm the main clinical features of this recognizable syndrome: universal DD with severe speech impediment, mild facial dysmorphism, and high frequency of craniofacial anomalies, behavioral issues, and brain neuroradiographic changes. As the recently proposed surveillance guidelines for individuals with SAS are adopted by providers, further delineation of the frequency and impact of other phenotypic traits will become available. Similarly, as new cases of SAS are identified, further exploration of genotype-phenotype correlations will be possible.

Tyrosine supplementation in phenylketonuria: diurnal blood tyrosine levels and presumptive brain influx of tyrosine and other large neutral amino acids.

UNLABELLED: Tyrosine supplementation has not consistently been found to improve neuropsychologic function in phenylketonuria (PKU), possibly because of failure to achieve adequate levels of tyrosine in the brain. OBJECTIVES: To evaluate blood levels achieved after tyrosine supplementation in treated PKU and calculate brain influxes of tyrosine and other large neutral amino acids before and with tyrosine supplementation. STUDY DESIGN: Ten subjects with PKU receiving a phenylalanine-restricted diet were studied over 48 hours; each received tyrosine supplementation (300 mg/kg) on day 2. Plasma phenylalanine and tyrosine were measured every 2 hours, and all free amino acids were measured every 6 hours. Brain influxes of tyrosine and other large neutral amino acids were calculated. RESULTS: Plasma tyrosine levels were low normal at baseline. With supplementation there was a substantial but unsustained rise in plasma tyrosine. Calculated brain influx of tyrosine was 27% +/- 19% of normal before supplementation, increasing to 90% +/- 58% of normal with supplementation. Nevertheless, calculated influx remained less than 70% of normal at 50% of the time points. The calculated brain influxes of all other large neutral amino acids except tryptophan were 20% to 40% of normal before and with tyrosine supplementation. CONCLUSIONS: Tyrosine supplementation in the diet for PKU produces marked but nonsustained increases in plasma tyrosine levels, with calculated brain influx that often remains suboptimal. This could explain the lack of consistent neuropsychologic benefit with tyrosine supplementation.

Mitochondrial neurogastrointestinal encephalomyopathy: diagnosis by rectal biopsy.

A 14-year-old girl with the mitochondrial neurogastrointestinal encephalopathy syndrome had an 8-year history of intestinal pseudoobstruction with abdominal pain, persistent vomiting, gastric and duodenal dilatation, and duodenal diverticulosis. The child appeared chronically malnourished and had severe growth failure. Multisystem involvement was evident with the presence of ptosis, external ophthalmoplegia, muscle wasting, peripheral neuropathy, and diffuse white matter disease seen on magnetic resonance imaging. Lactic acidosis and increased cerebrospinal fluid protein were observed. Mitochondrial enzyme analysis of fresh-frozen skeletal muscle revealed a respiratory chain defect. Molecular genetic studies showed multiple mitochondrial DNA deletions. Pathologic findings in the intestine included atrophy of the external layer of the muscularis propria and an increased number of abnormal-appearing mitochondria in ganglion and smooth-muscle cells. Microvesicular steatosis was observed in liver, skeletal, and gastrointestinal smooth muscle, and Schwann cells of peripheral nerve. Brightly eosinophilic inclusions in the cytoplasm of gastrointestinal ganglion cells were visible by light microscopy, which were confirmed to be megamitochondria by ultrastructural studies. This is the first report of abnormal mitochondria observed in intestinal ganglion and smooth-muscle cells in this syndrome.