PMC6788382_01
Pedigree. The patient and his fourth brother showed heterozygous mutations in exon12 encoding PAH c.1068C>A and c.740G>T in WES, while the youngest brother was a carrier with only c.1068C>A. Other family members were roughly identified by positive clinical manifestations. No consanguineous marriage in this family.
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F2
Family medical history revealed six of his family members suffered from mental retardation (Figure 2). We conducted whole exome sequencing (WES) on the patient and his two younger brothers (Figure 2: The fourth and eighth brothers), and the results revealed mental retardation in the patient and his younger brother showing heterozygous mutations in exon12 encoding PAH c.1068C>A and c.740G>T without mutation in the BH4-relating genome, while the youngest brother was a carrier with only c.1068C>A.
The axial sequences on head MRI of the patient (A-F) and The head CT of the sick brother (G,H). (A-F) Bilateral symmetric diffuse white matter hyperintensity, predominantly involving the frontal, parietal, occipital, and periventricular regions on T2WI (A,B) and FLAIR (C,D), with restriction in peripheral areas of lesions on DWI (E,F), whereas normal on ADC map. The U-fibers of bilateral occipital lobe and the white matter of paracortical, subcortical were involved but corpus callosum and internal capsule were relatively reserved. There was atrophy in temporal and frontal lobes, especially significant in frontal pole. (G,H) The low-density lesions around bilateral ventricles mainly involving white matter around the posterior horn of lateral ventricles, with atrophy of temporal and frontal lobes especially in frontal pole.
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F3
The axial T2-weighted magnetic resonance imaging (T2WI) and Fluid Attenuated Inversion Recovery (FLAIR) sequences on brain MRI revealed bilateral symmetric diffuse white matter hyperintensity, predominantly involving the frontal, parietal, occipital, and periventricular regions with restriction in peripheral areas of lesions on diffusion weighted imaging (DWI) (Figures 3A-C,E-G). We managed to get the head CT of the patient's sick brother concurrently and the results suggested the existence of low-density lesions in the bilateral frontal and posterior horn of lateral ventricle but comparably milder than patient (Figures 3D,H).
Urine organic acid spectrum showed that phenylacetic acid, phenyllactic acid and Phenylpyruvate increased, suggesting hyperphenylalanine; 2.4-hydroxyphenyllactic acid increased, which may be secondary to liver function damage.
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F4
We instigated urine and plasma amino acid with urine organic acid and plasma acylcarnitine analyses to report the markedly elevated Phe levels (1221.5 muM, normal < 120 muM) and Phe/Tyr ratio (27.45, normal 0.30-2.00) in serum and increased phenyllactic acid and phenylketone acid in urine (Figure 4), consistent with cPKU.