PMC7750521_01
Clinical features and uridine response of patient 1 with CAD deficiency. (A) Family pedigree of patient 1. (B) Brain MRI at 10-months. Peripheral blood smear (C) before treatment and (D) after treatment. (E) Clinical overview during the course of disease. Gross motor development represented as the observed development age according to the Nelson Gross Motor Development Milestones divided by the patient's biological age.
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F1
The ictal VEEG at 9-months recorded sharp (spike) slow wave discharges while monitoring a seizure attack (eyes turned right, salivating, with right limbs stiffness and shaking), and the interictal EEG documented sharp and spike slow wave in the bilateral occipitotemporal lobe (Supplementary Figure S1C). A sequential interictal VEEG at 1-year of age recorded no epileptiform discharge, except for few atypical sharp waves in the left posteromedial temporal lobe during sleep without epileptiform discharge (Supplementary Figure S1D).
PMC7750521_02
Clinical features and uridine response of patient 1 with CAD deficiency. (A) Family pedigree of patient 1. (B) Brain MRI at 10-months. Peripheral blood smear (C) before treatment and (D) after treatment. (E) Clinical overview during the course of disease. Gross motor development represented as the observed development age according to the Nelson Gross Motor Development Milestones divided by the patient's biological age.
fphar-11-608737-g001.jpg
PMC7750521_02_fphar-11-608737-g001.jpg
F1
The ictal VEEG at 9-months recorded sharp (spike) slow wave discharges while monitoring a seizure attack (eyes turned right, salivating, with right limbs stiffness and shaking), and the interictal EEG documented sharp and spike slow wave in the bilateral occipitotemporal lobe (Supplementary Figure S1C). A sequential interictal VEEG at 1-year of age recorded no epileptiform discharge, except for few atypical sharp waves in the left posteromedial temporal lobe during sleep without epileptiform discharge (Supplementary Figure S1D).
Clinical features and uridine response of patient 2 with CAD deficiency. (A) Family pedigree of patient 2. (B) Brain MRI at 8.5-months. Peripheral blood smear (C) before treatment and (D) after treatment. (E) Clinical overview during the course of disease. Gross motor development represented as the observed development age according to the Nelson Gross Motor Development Milestones divided by the patient's biological age.
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F2
Patient 2 is a girl currently 17-months of age, born at term to a healthy nonconsanguineous family and fed by both breast and formula milk (Figure 2A). The brain MRI performed at 8.5-months was unremarkable (Figure 2B). Her whole blood cell count indicated mild anaemia (haemoglobin 10-10.5, reference 11-16 g/dl; mean corpuscular volume 79.4-82.9, reference range 80-100 fl) and the peripheral blood smear showed abnormal erythrocytes of varying size and morphology, suggestive of anaemia with anisopoikilocytosis (Figure 2C). Routine blood tests and the peripheral blood smear both normalised (Figure 2D). Moreover, she has made further significant progress in global development, and is now able to walk with assistance and speak one to two words, such as "mama" and "I want." Her clinical course is depicted in Figure 2E.
PMC7750521_03
Gene results of two patients with CAD deficiency. (A,B) Sanger sequencing of our two cases demonstrated CAD compound heterozygous variants. (C) Location of CAD variants. (D) Evolutionary conservations of the missense mutations (A1517, V1226, and D982).
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F3
As for patient 2, the identified variant, c.4549G>C (p.A1517P), was interpreted as likely pathogenic, while c.6421_6422insTGCT (p.Y2143AfsTer67) was predicted as VUS (Figures 3A,B). The location of the novel variants in functional domains and their high-degree of conservation is depicted in (Figure 3C). According to sequence alignment, the amino acids A1517, V1226, and D982 are highly conserved across species, indicating evolutionary importance (Figure 3D).