BACKGROUND

Six-pyruvoyl-tetrahydrobiopterin synthase (6-PTPS) deficiency is an inherited metabolic disorder which results in tetrahydrobiopterin (BH4) deficiency causing hyperphenylalaninemia.

This study aimed to describe the clinical, biochemical, and radiologic profiles, and neurologic and developmental outcomes of patients diagnosed with 6-pyruvoyl tetrahydrobiopterin (PTPS) deficiency through newborn screening and confirmed by BH4 loading test, pterin analysis, and gene sequencing who were following-up with the metabolic team.

The research was a single-center descriptive case series study design that was done at the Philippine General Hospital, a tertiary government hospital. The clinical, biochemical, radiologic profiles and neurodevelopmental evaluation of each patient were described.

Nine patients from 1 year 2 months to 14 years 5 months of age were enrolled in the study. Clinical manifestations before treatment were hypotonia, poor suck, and seizure. The most common clinical manifestation even after treatment initiation was seizure. The mean phenylalanine level on newborn screening was 990.68 umol/L, but after treatment was started, mean levels ranged from 75.69 to 385.09 umol/L. Two of the patients had focal atrophy of the posterior lobe on brain imaging. Pathogenic variants on molecular analysis were all missense, with two predominant variants, c.155A>G and c.58T>C. Eight of the nine patients had varying degrees of developmental delay or intellectual disability, while the remaining patient had signs of a learning disorder.

Newborn screening has played a crucial role in the early identification and management of patients with hyperphenylalaninemia due to 6-PTPS deficiency. Confirmation of diagnosis through determination of DHPR activity, urine pterins and/or molecular analysis is necessary for appropriate management. However, despite early initiation of treatment, neurodevelopmental findings of patients with 6-PTPS deficiency were still unsatisfactory.

BACKGROUND

The migration from classroom learning to real patient encounters during clinical clerkship is a transformative journey that carries with it many challenges which serve as rich sources of meaning. The actual patient interactions are pivotal opportunities that provide transcendental meanings which contribute to the well-rounded development of medical clerks, ultimately enhancing their ability to deliver better patient care.

Utilizing a qualitative phenomenological approach, the study allowed exploration of intricate layers of meaning embedded within the encounters of three female medical clerks in a medical university hospital in Manila, Philippines. The gathered narratives were analyzed and meanings were derived from these statements. The identified meanings were then organized into themes and essential insights that represented the core essence of the phenomenon being studied.

The reflections extracted from narratives revealed the emergence of 10 significant major themes stemming from medical clerks’ patient encounters. These encounters were consistently described as a sacred responsibility, providing opportunities for profound connections, resilience, deepened faith and comprehensive personal and professional development within a caring and compassionate environment.

The transformative journey was marked by profound personal and spiritual growth among medical clerks. Beyond developing their clinical skills, they experienced a transcendence that spoke to human desire for meaning beyond the material world. This "spirituality of encounter" fostered deeper connections with patients and enriched their perspectives on clinical practice that can further enhance their holistic development as medical students.

Background: Six-pyruvoyl-tetrahydrobiopterin synthase (6-PTPS) deficiency is an inherited metabolic disorder which results in tetrahydrobiopterin (BH4) deficiency causing hyperphenylalaninemia. Objective: This study aimed to describe the clinical, biochemical, and radiologic profiles, and neurologic and developmental outcomes of patients diagnosed with 6-pyruvoyl tetrahydrobiopterin (PTPS) deficiency through newborn screening and confirmed by BH4 loading test, pterin analysis, and gene sequencing who were following-up with the metabolic team. Methods: The research was a single-center descriptive case series study design that was done at the Philippine General Hospital, a tertiary government hospital. The clinical, biochemical, radiologic profiles and neurodevelopmental evaluation of each patient were described. Results: Nine patients from 1 year 2 months to 14 years 5 months of age were enrolled in the study. Clinical manifestations before treatment were hypotonia, poor suck, and seizure. The most common clinical manifestation even after treatment initiation was seizure. The mean phenylalanine level on newborn screening was 990.68 umol/L, but after treatment was started, mean levels ranged from 75.69 to 385.09 umol/L. Two of the patients had focal atrophy of the posterior lobe on brain imaging. Pathogenic variants on molecular analysis were all missense, with two predominant variants, c.155A>G and c.58T>C. Eight of the nine patients had varying degrees of developmental delay or intellectual disability, while the remaining patient had signs of a learning disorder. Conclusion Newborn screening has played a crucial role in the early identification and management of patients with hyperphenylalaninemia due to 6-PTPS deficiency. Confirmation of diagnosis through determination of DHPR activity, urine pterins and/or molecular analysis is necessary for appropriate management. However, despite early initiation of treatment, neurodevelopmental findings of patients with 6-PTPS deficiency were still unsatisfactory.

OBJECTIVE: This study reviewed the profiles and outcomes of patients diagnosed to have the five most common inherited metabolic diseases (IMDs) in the Metabolic Registry of the National Institutes of Health - Institute of Human Genetics (NIH-IHG) from 1999 to 2016.

METHODS: The medical records of the patients diagnosed with the following inherited metabolic diseases were reviewed: maple syrup urine disease (MSUD), galactosemia, hyperphenylalaninemias (including classical phenylketonuria, mild hyperphenylalaninemia, and pterin defects), mucopolysaccharidoses (MPS), and adrenoleukodystrophy (ALD).

RESULTS: There was a total of 567 patients with IMDs, giving a minimum estimated burden of 1.9 per 100,000 livebirths (1:51,760). Clinical presentations were similar to those reported in literature. Majority of the cases of galactosemia and hyperphenylalaninemias presented with a positive newborn screening result. The local prevalence of MSUD and MPS II were higher compared to international data, which may be explained by reported founder mutations among Filipinos. Majority of the patients with IMDs were diagnosed late leading to preventable developmental delay or intellectual disability and death. Majority of patients with MSUD (80.6%) and MPS (94.7%) had intellectual disability or developmental delay. Mortality was 50.5% among patients with MSUD and 100% among patients with adrenoleukodystrophy.

CONCLUSION: There is a diversity of IMDs present in the country. A long-term strategic plan, such as the full implementation of the National Rare Disease Act, is foreseen to improve access to comprehensive healthcare and quality of life of patients with IMDs in the country.

Objective: The study is a retrospective review which provides preliminary data on the correlation between biochemical profiles and initial clinical manifestation of patients diagnosed to have argininosuccinate synthetase deficiency (ASSD) and argininosuccinate lyase deficiency (ASLD) detected by expanded newborn screening (ENBS). Methods: This is a study of five distal UCD patients initially detected by elevated citrulline on ENBS. Medical charts of the patients were reviewed. The initial clinical manifestations of the patients were correlated with results of biochemical tests. Results: There were four cases of ASLD and one case of ASSD reviewed in this study. All cases of ASLD were confirmed by the presence of argininosuccinic acid (ASA) in the urine metabolic screen (UMS). The plasma citrulline level of the ASSD patient is significantly elevated as compared to the ASLD patients (2,690 µmol/L; NV: 10-45 µmol/L). The ASSD patient and one ASLD patient were symptomatic within the first six days of life. Both presented with significantly elevated plasma ammonia, citrulline and glutamine levels. Three ASLD patients were asymptomatic on initial screening. Conclusion ENBS has shown importance in the early detection and management of ASSD and ASLD. Early initiation of management may prevent hyperammonemic crises. Long term outcome studies are needed to look into the correlation of neurodevelopmental outcome with lifelong accumulation of citrulline and glutamine in ASSD and ASA in ASLD.
Citrullinemia ; Argininosuccinic Aciduria ; Argininosuccinic Acid

Introduction: Glutaric Aciduria Type 1 (GA1) is an inborn error of metabolism included in the expanded newborn screening of the Philippines. This inborn error of metabolism is caused by glutaryl-CoA dehydrogenase deficiency which is important in the catabolism of lysine, hydroxylysine and tryptophan. Objective: This paper aimed to present the baseline data of patients with GA1 in the Philippines by describing the clinical, biochemical, and radiologic characteristics of Filipino patients with biochemically-confirmed GA1 seen at the Philippine General Hospital from January 2010 to December 2017. The cases of this condition have been increasing and are expected to increase even more with the full coverage of the expanded newborn screening. Methods: This study was a review of the medical records of the GA1 patients managed by the Division of Clinical Genetics, Department of Pediatrics of the Philippine General Hospital (PGH). Biochemical parameters, developmental assessment, neurologic assessment, and radiologic features of the patients were reviewed and analyzed. Results: There were a total of 7 patients with GA1 at the PGH from January 2010 to December 2017. Of the 7 patients, 4 were diagnosed by expanded newborn screening (ENBS) and 3 patients had disease onset prior to diagnosis. Clinical features noted in screened patients include global developmental delay (75%), seizures (50%), dystonia (50%), truncal hypotonia (25%) and macrocephaly (25%). In unscreened patients, macrocephaly was present in 66.67 %, while the other clinical features were present in all of them. Four of the 7 patients had infection and one had vaccination, which may have led to a metabolic crisis and subsequent onset of symptoms. The plasma levels of glutarylcarnitine (C5DC) range from 2.81 to 4.58 umol/L. Grossly elevated urinary excretion of glutarylcarnitine were noted in all patients. Urinary glutaconic acid and 3-hydroxyglutaric acid were also detected in all patients. Both striatal and extra-striatal abnormalities were present in screened and unscreened patients on neuroimaging. The most common being the widening of the sylvian fissure, cerebral atrophy, and white matter abnormalities. Conclusion Although newborn screening of GA1 and initiation of early management of this condition have been seen important, it is still prudent to continue the appropriate management and to provide timely aggressive emergency treatment in order to improve outcome of patients with GA1. With the recent Philippine Health Insurance (PhilHealth) coverage of the expanded newborn screening, it is expected that physicians will encounter more of the metabolic disorders, including GA1. Hence, it is important that physicians be more aware of the presenting signs and symptoms of this disorder, as well as its management, which can further improve the neurologic and developmental outcomes of these patients.
Neonatal Screening

Saving babies from mental retardation and death is the aim of the newborn screening program. A complex process of sample collection, processing and feedback is undertaken before reaching this goal. As with other systems, the newborn screening program is not perfect and periodic review is needed to continually improve services. Using maple syrup urine disease (which is the most common inborn error of metabolism detected through newborn screening) as an index case, this paper aims to present the gaps in diagnosis and management by citing cases and providing a commentary.
Maple Syrup Urine Disease ; Neonatal Screening

Background. X-linked adrenoleukodystrophy (X-ALD) is a progressive genetic disorder affecting the metabolism of very long chain fatty acids in the adrenal glands, spinal cord and white matter of the nervous system. It is an inherited metabolic storage disease whereby a defect in a specific enzyme results in the accumulation of very long-chain fatty acids (VLCFA) that are harmful to some cells and organs. VLCFA analysis for confirmation of X-linked adrenoleukodystrophy is one of the most requested tests among the send-out laboratory services of the Biochemical Genetics Laboratory at the Institute of Human Genetics. This paper aims to review the clinical characteristics and the results of the VLCFA analysis of the patients whose samples we received for testing.Methods. Overseas tests samples received by the Biochemical Genetics Laboratory for VLCFA from 2002-2016 were included. The details of the patients were collated in an overseas tests database and was the main source of the data for this study. The results of the VLCFA tests sent to the Kennedy Krieger Institute and The Children’s Hospital at Westmead were inputted into the said database. Descriptive statistics was utilized in order to examine the clinical and biochemical data of the patients.Results. The results showed that out of the 54 samples submitted to our laboratory, 19 (35%) of the samples received from male patients suspected to have X-ALD yielded positive results and another 10 (19%) females were found to be carriers. Visual defect followed by deteriorating mental status were the most frequent indications for VLCFA testing. Conclusion. Having a significant diagnostic yield of 54%, early diagnosis of X-linked adrenoleukodystrophy in our population is important so that proper management that could prevent the progression of the disease could be timely instituted.
Metabolism, Inborn Errors ; Peroxisomal Disorders ; Adrenoleukodystrophy

Gaucher disease is the most common of the lysosomal storage diseases caused by a defect in the lysosomal enzyme βglucocererbrosidase resulting in multi-organ involvement. The presence of cholelithiasis has been rarely observed among patients with non-neuronopathic type of Gaucher disease and the exact pathophysiology is still unknown. We report a Filipino child with chronic neuronopathic Gaucher Disease noted to have cholelithiasis on routine whole abdominal ultrasonography as part of the regular monitoring of the disease.
Gaucher Disease ; Cholelithiasis ; Gaucher Disease

The neuronal ceroid lipofuscinoses correspond to a group of disorders characterized by neurodegeneration and intracellular buildup of auto-flourescent lipopigment (ceroid lipofuscin). They are classified by age of onset into infantile, late infantile, juvenile and adult forms. Among these, the late infantile type is caused by mutations in tripeptidyl peptidase 1 (TPP1) gene and is characterized by age of onset between 2-4 years, seizures, early progressive cognitive impairment and visual loss. Our patient is a 4-year-old girl who presented at 2 years and 10 months old with seizures followed by ataxia, regression of skills and eventual visual decline. TPP1 enzyme activity was below normal for age. This report aims to increase the awareness of physicians on the cluster of symptoms characteristic of this disorder which will help facilitate early diagnosis and prompt institution of appropriate management.
Neuronal Ceroid-Lipofuscinoses ; Cognitive Dysfunction