Long-term neurocognitive function of pediatric patients with severe combined immune deficiency (SCID): pre- and post-hematopoietic stem cell transplant (HSCT).

BACKGROUND:Hematopoietic stem cell transplantation (HSCT) is the only cure for patients with severe combined immunodeficiency (SCID). The purpose of this study was to evaluate long-term neurodevelopment of patients with SCID following myeloablative chemotherapy and HSCT. MATERIALS AND METHODS:Sixteen pediatric patients diagnosed with SCID were tested using the Bayley Scales of Infant Development and the validated Vineland Adaptive Behavior Scales (VABS) pre- and 1-year post-HSCT. Three years post-HSCT, there were 11 patients available for testing and four patients available 5 years post-HSCT. Patients greater than 3 years of age were administered the Wechsler Preschool and Primary Scale of Intelligence. Both raw scores and scaled scores were analyzed. RESULTS:There was a significant decrease 1 year post-HSCT in the Bayley Mental Developmental Index (MDI) [92.5 (pre) vs. 70.81 (1 year post), p < 0.0001] and the VABS [99.73 (pre) vs. 79.87 (1 year post), p = <0.0001]. There was a significant decrease over time in the MDI [95.00 (pre) vs. 72.64 (1 year post) vs. 71.82 (3 years post), p < 0.0001], but no significant change between 1 and 3 years post-HSCT. There was no change in the Bayley Psychomotor Development Scale (PDI) [82.4 (pre) vs. 84.8 (1 year post), p = 0.68]. The PDI scores decreased over time [86.29 (pre) vs. 86 (1 year post) vs. 74.14 (3 years post), p = 0.045]. Although there was a decrease in scaled scores, there was not a loss of skills. Analysis of raw scores showed that there was an increase in the raw test scores, which indicated that these children acquired developmental skills, but at a slower rate than normal infants and toddlers. Younger children had a more significant decrease in adaptive scores compared with older children. CONCLUSIONS:These findings may reflect the effects of the isolation and prolonged hospitalization that characterizes the immediate post-transplant period. Patients miss out on social interactions and learning opportunities that normally occur at their respective stages of development. These restrictions keep patients from acquiring developmentally appropriate cognitive skills as well as gross and fine motor developmental milestones. Longitudinal follow-up will be important to quantify acquisition of skills

Relationship of Acute Phase Reactants and Fat Accumulation during Treatment for Tuberculosis

Background. Tuberculosis causes inflammation and muscle wasting. We investigated how attenuation of inflammation relates to repletion of body composition during treatment in an underserved population. Design. Twenty-four patients (23 to 79 years old) with pulmonary tuberculosis and inflammation (pretreatment albumin = 2.96 ± 0.13 g/dL, C-reactive protein [CRP] = 6.71 ± 1.34 μg/dL, and beta-2-microglobulin = 1.68 ± 0.10 μg/L) were evaluated and had BIA over 24 weeks. Results. Weight increased by 3.02 ± 0.81 kg (5.5%; P = 0.007) at week 4 and by 8.59 ± 0.97 kg (15.6%; P < 0.0001) at week 24. Repletion of body mass was primarily fat, which increased by 2.09 ± 0.52 kg at week 4 and 5.05 ± 0.56 kg at week 24 (P = 0.004 and P < 0.0001 versus baseline). Fat-free mass (FFM), body cell mass (BCM), and phase angle did not increase until study week 8. Albumin rose to 3.65 ± 0.14 g/dL by week 4 (P < 0.001) and slowly increased thereafter. CRP levels declined by ∼50% at each interval visit. Conclusions. During the initial treatment, acute phase reactants returned towards normal. The predominant accrual of fat mass probably reflects ongoing, low levels of inflammation

Evaluation of Tetrahydrobiopterin Therapy with Large Neutral Amino Acid Supplementation in Phenylketonuria: Effects on Potential Peripheral Biomarkers, Melatonin and Dopamine, for Brain Monoamine Neurotransmitters

<div><p>Background</p><p>Phenylketonuria (PKU) is due to a defective hepatic enzyme, phenylalanine (Phe) hydroxylase. Transport of the precursor amino acids from blood into the brain for serotonin and dopamine synthesis is reported to be inhibited by high blood Phe concentrations. Deficiencies of serotonin and dopamine are involved in neurocognitive dysfunction in PKU.</p><p>Objective</p><p>(1) To evaluate the effects of sapropterin (BH4) and concurrent use of large neutral amino acids (LNAA) on the peripheral biomarkers, melatonin and dopamine with the hypothesis they reflect brain serotonin and dopamine metabolism. (2) To evaluate synergistic effects with BH4 and LNAA. (3) To determine the effects of blood Phe concentrations on the peripheral biomarkers concentrations.</p><p>Methods</p><p>Nine adults with PKU completed our study consisting of four 4-week phases: (1) LNAA supplementation, (2) Washout, (3) BH4 therapy, and (4) LNAA with BH4 therapy. An overnight protocol measured plasma amino acids, serum melatonin, and 6-sulfatoxymelatonin and dopamine in first void urine after each phase.</p><p>Results</p><p>(1) Three out of nine subjects responded to BH4. A significant increase of serum melatonin levels was observed in BH4 responders with decreased blood Phe concentration. No significant change in melatonin, dopamine or Phe levels was observed with BH4 in the subjects as a whole. (2) Synergistic effects with BH4 and LNAA were observed in serum melatonin in BH4 responders. (3) The relationship between serum melatonin and Phe showed a significant negative slope (p = 0.0005) with a trend toward differing slopes among individual subjects (p = 0.066). There was also a negative association overall between blood Phe and urine 6-sulfatoxymelatonin and dopamine (P = 0.040 and 0.047).</p><p>Conclusion</p><p>Blood Phe concentrations affected peripheral monoamine neurotransmitter biomarker concentrations differently in each individual with PKU. Melatonin levels increased with BH4 therapy only when blood Phe decreased. Monitoring peripheral neurotransmitter metabolites may assist in optimizing individualized treatment in PKU.</p></div

Characteristics of Study Subjects.

<p>Characteristics of Study Subjects.</p

Evaluation of Tetrahydrobiopterin Therapy with Large Neutral Amino Acid Supplementation in Phenylketonuria: Effects on Potential Peripheral Biomarkers, Melatonin and Dopamine, for Brain Monoamine Neurotransmitters - Fig 1

<p><b>Overnight serum melatonin AUC (A) and Plasma phenylalanine concentrations (B) over the 4 phases.</b> Phase 1 (LNAA), Phase 2 (Washout), Phase 3 (BH4) and Phase 4 (BH4 + LNAA). A1 and B1: BH4 responders. A2 and B2: BH4 non-responders. All BH4 responders showing significant decrease in plasma Phe levels, increased serum melatonin (Phase 3 vs. Phase 2 and Phase 4 vs. Phase 1). BH4 non-responders did not show increases in serum melatonin levels (Phase 3 vs Phase 2 and Phase 4 vs. Phase 1). All BH4 responders and S2, S5, S6, and S9 (4 out of 6 subjects) increased serum melatonin with LNAA (Phase 2 vs. Phase 1). All BH4 responders and S2, S5, S6, S7, and S9 (5 out of 6 subjects) increased serum melatonin with BH4 and LNAA over BH4 only (Phase 4 vs. Phase 3).</p

Urine dopamine vs. Plasma phenylalanine.

<p>The number of each data point indicates the study phase. Negative correlations with plasma phenylalanine concentrations and urine dopamine (p = 0.047) are shown. Except for S7, a linear negative regression line is drawn for each subject.</p

Serum Melatonin (AUC) vs. Plasma Phenylalanine.

<p>The number of each data point indicates the study phase. Negative correlations with plasma phenylalanine concentrations and serum melatonin AUC (p = 0.0005) is shown. Except for S8, a linear negative regression line is drawn for each subject. The slope of linear regression line differs among the 9 subjects (p = 0.066).</p

Urine 6-sulfatoxymelatonin (C) and Urine dopamine concentrations (D) over the 4 phases.

<p>Phase 1 (LNAA), Phase 2 (Washout), Phase 3 (BH4) and Phase 4 (BH4+LNAA). C1 and D1: BH4 responders. C2 and D2: BH4 non-responders. The data point at Phase 4 in S3 is missing due to sample collection failure.</p

Serum melatonin AUC, urine 6-sulfatoxymelatonin, Phe, and urine dopamine levels at the end of each phase.

<p>Serum melatonin AUC, urine 6-sulfatoxymelatonin, Phe, and urine dopamine levels at the end of each phase.</p