Rubinstein-Taybi Syndrome in a Filipino Infant with a Novel CREBBP Gene Pathogenic Variant.

Rubinstein-Taybi syndrome (RSTS) is a rare genetic disorder characterized by dysmorphic facial features, broad thumbs and halluces, intellectual disability, and postnatal growth retardation. This report presents a male infant with microcephaly and characteristic facial features, namely, low anterior hairline, hirsutism, thin upper lip and micrognathia, broad thumbs and first toes, cryptorchidism, recurrent pneumonia, developmental delay, and growth retardation. Genetic testing showed a novel pathogenic variant in the CREBBP gene which is consistent with the clinical diagnosis of RSTS.

Successful Implementation of Expanded Newborn Screening in the Philippines Using Tandem Mass Spectrometry.

Newborn bloodspot screening (NBS) began as a research project in the Philippines in 1996 and was mandated by law in 2004. The program initially included screening for five conditions, with a sixth added in 2012. As screening technology and medical knowledge have advanced, NBS programs in countries with developed economies have also expanded, not only in the number of newborns screened but also in the number of conditions included in the screening. Various approaches have been taken regarding selection of conditions to be screened. With limited resources, low- and middle-income countries face significant challenges in selecting conditions for screening and in implementing sustainable screening programs. Building on expansion experiences in the U.S. and data from California on Filipinos born and screened there, the Philippine NBS program has recently completed its expansion to include 29 screening conditions. This report focuses on those conditions detectable through tandem mass spectrometry. Expanded screening was implemented in a stepwise fashion across the seven newborn screening laboratories in the Philippines. A university-based biochemical genetics laboratory provides confirmatory testing. Follow-up care for confirmed cases is monitored and provided through the NBS continuity clinics across the archipelago. Pre-COVID-19 pandemic, the coverage was 91.6% but dropped to 80.4% by the end of 2020 due to closure of borders between cities, provinces, and islands.

A review of the clinical outcomes in idursulfase-treated and untreated Filipino patients with mucopolysaccharidosis type II: data from the local lysosomal storage disease registry.

BACKGROUND: Mucopolysaccharidosis type II (MPS II; Hunter syndrome) is an X-linked multisystem disorder characterized by glycosaminoglycan (GAG) accumulation, caused by a deficiency of iduronate-2-sulfatase (I2S). Enzyme replacement therapy (ERT) with recombinant idursulfase (IDS), the standard of care, was started in the Philippines in 2017. This study reviewed the clinical outcomes in idursulfase-treated and untreated Filipino MPS II patients who were included in the local Lysosomal Storage Disease (LSD) registry of the Institute of Human Genetics-National Institutes of Health (IHG-NIH) from January 1999 to December 2019. METHODS: A retrospective audit of records of MPS II patients listed in the registry was done. Qualified patients were divided into two cohorts: idursulfase-treated group (patients on enzyme replacement therapy, ERT, for ≥ 6 months) and untreated group. Baseline characteristics, including demographic data, biochemical results, neurocognitive classification, respiratory involvement, mortality, and adverse events, were recorded. Height, weight, cardiac pathology, liver and spleen sizes, six-minute walking test (6MWT), joint mobility, were determined at baseline and at year 1 and 2 of follow up. RESULTS: Forty male patients were included in this review, with only 8 receiving ERT since 2017. The mean age at diagnosis was 6.99 years (SD 4.15; 0.75-20) and mean age at start of ERT was 14.03 years (SD 7.1; 4-21.5), more delayed than previous reports. Eighty percent have early progressive phenotype which was higher than reported average. The early growth pattern differed in our Filipino cohort, but was followed by the expected slowed growth in later years. Improvements in the following endpoints were observed in the treated cohort: height and weight, cardiac disease, liver and spleen sizes, and joint mobility. There were also positive effects on respiratory involvement and mortality rate. Adverse events were consistent with previous reports. CONCLUSIONS: ERT is generally well tolerated and effective in reducing GAG storage and improving clinical endpoints among our Filipino MPS II patients. In untreated patients, typical disease progression was observed.

Maple syrup urine disease associated with nephrotic syndrome in a Filipino child.

A 22-month-old female child with maple syrup urine disease (MSUD) presented with generalised oedema. Diagnostic evaluation revealed nephrotic range proteinuria, hypoalbuminaemia and dyslipidaemia supporting the diagnosis of nephrotic syndrome (NS). Diet, being at the core of the management plan for both MSUD and NS, necessitated regular monitoring and evaluation via dried blood spot collection of leucine. The opposing requirement for total protein for both disorders (that is protein restriction in MSUD and protein supplementation in NS) prompted a careful balancing act of the dietary management. The monitoring, which revealed normal leucine levels on multiple determinations, allowed an eventual increase in dietary protein and daily administration of albumin to address the NS. Dietary protein increase, both in total protein (3.5 g/kg/day) and natural protein (1 g/kg/day) levels, was instituted. It was observed that NS does not trigger leucinosis and allowed easing of protein restriction in MSUD.

Genetic and clinical characteristics of Filipino patients with Gaucher disease.

Gaucher disease (GD) is a lysosomal storage disorder caused by the deficiency of the ß-glucocerebrosidase enzyme due to disease causing mutations in the GBA1 (glucosidase beta acid) gene, leading to the abnormal accumulation of the lipid glucocerebroside in lysosomal macrophages. This is a review of the clinical features and molecular profiles of 14 Filipino patients with GD. Five patients presented with type 1 disease, two had type 2 GD and seven had type 3 GD. The age of onset for all types was between 1 and 2 years of age but there was a delay of 2.2 years from the time of symptom onset to confirmation of diagnosis. Hepatosplenomegaly, anemia and thrombocytopenia were present in most of the patients. Stunting was seen in 64.3% and bone abnormalities were present in 63.6%. The most common mutant allele detected in this cohort was L483P (previously L444P), followed by F252I, P358A and G241R. IVS2+1 G>A, N409S and G416S mutations were reported singularly. There were 3 patients who were found to have N131S mutations and one patient with D257V mutation, mutant alleles that have only been reported among the Filipinos to date. Except for N409S, the mutations found in this cohort were generally severe and were congruent with the severe phenotypes found in most patients. Of the 14 patients, only 6 were able to undergo enzyme replacement therapy which significantly improved the hematologic parameters and decreased the sizes of the liver and spleen but did not consistently improve the growth and skeletal abnormalities nor alleviate the neurological manifestations of our patients with GD. Improved monitoring through recommended modalities for assessments and tools for evaluation should be implemented in order to fully appreciate the severity of the disease and accuracy of the response to treatment.

Clinical, biochemical and molecular characteristics of Filipino patients with mucopolysaccharidosis type II - Hunter syndrome.

BACKGROUND: Mucopolysaccharidosis type II, an X-linked recessive disorder is the most common lysosomal storage disease detected among Filipinos. This is a case series involving 23 male Filipino patients confirmed to have Hunter syndrome. The clinical and biochemical characteristics were obtained and mutation testing of the IDS gene was done on the probands and their female relatives. RESULTS: The mean age of the patients was 11.28 (SD 4.10) years with an average symptom onset at 1.2 (SD 1.4) years. The mean age at biochemical diagnosis was 8 (SD 3.2) years. The early clinical characteristics were developmental delay, joint stiffness, coarse facies, recurrent respiratory tract infections, abdominal distention and hernia. Majority of the patients had joint contractures, severe intellectual disability, error of refraction, hearing loss and valvular regurgitation on subspecialists' evaluation. The mean GAG concentration was 506.5 mg (SD 191.3)/grams creatinine while the mean plasma iduronate-2-sulfatase activity was 0.86 (SD 0.79) nmol/mg plasma/4 h. Fourteen (14) mutations were found: 6 missense (42.9%), 4 nonsense (28.6%), 2 frameshift (14.3%), 1 exon skipping at the cDNA level (7.1%), and 1 gross insertion (7.1%). Six (6) novel mutations were observed (43%): p.C422F, p.P86Rfs*44, p.Q121*, p.L209Wfs*4, p.T409R, and c.1461_1462insN[710]. CONCLUSION: The age at diagnosis in this series was much delayed and majority of the patients presented with severe neurologic impairment. The results of the biochemical tests did not contribute to the phenotypic classification of patients. The effects of the mutations were consistent with the severe phenotype seen in the majority of the patients.

Challenges in the management of patients with maple syrup urine disease diagnosed by newborn screening in a developing country.

Maple syrup urine disease (MSUD) is a rare inborn error of metabolism resulting from a deficiency in the branched-chain alpha-ketoacid dehydrogenase complex. MSUD has been reported to be the most common inborn error of metabolism in the Philippines. We described all patients with maple syrup urine disease patients diagnosed through newborn screening during its first 2 years of implementation and the challenges encountered during their medical management. There were 24 patients diagnosed with maple syrup urine disease for the 2-year period. All patients needed hospital admission. The most common complication during hospital admission was infection, needing intravenous antibiotics which were given to 21 of the patients. Out of the 24 diagnosed, 16 patients are alive, while eight have died. Several neurologic and non-neurologic complications have been observed during the follow-up of the patients. The common challenges of MSUD management in a low-resource setting identified in this study were late diagnosis, lack of access to metabolic specialists and medical supplies, nosocomial septicemia, and protein deficiency. Aside from early properly timed collection, improvement in other logistical concerns will also help in earlier diagnosis. Mechanisms of transfer of critically ill patients must be improved. Hospitals in difficult-to-reach areas must be equipped to handle critical metabolic cases when transfers are not possible. Newborn screening has been proven to improve outcome in patients with MSUD but the success of the program in preventing disability is also dependent on improvements in other aspects of healthcare.

Plasma amino acid and urine organic acid profiles of Filipino patients with maple syrup urine disease (MSUD) and correlation with their neurologic features.

BACKGROUND: Maple syrup urine disease (MSUD) is the most common inborn error of metabolism in the country. The cause of the neuropathology is still not well established although accumulation of branched chain amino acids (BCAA) and alteration in large neutral amino acids (LNAA) as well as energy deprivation are suggested. It is therefore the aim of this study to determine the plasma amino acid and urine organic acid profiles of patients with MSUD and correlate the findings with their neurologic features. METHODOLOGY: Twenty six Filipino patients with MSUD were studied in terms of their plasma amino acid and urine organic acid profiles. Their results were compared with 26 age and sex matched controls. The neurologic features were correlated with the results of the plasma amino acids and urine organic acids. RESULTS: Majority of the patients with MSUD had developmental delay/intellectual disability (88%), speech delay (69%), and seizures (65%). Their amino acid profiles revealed low glutamine and alanine with high levels of leucine, isoleucine, phenylalanine, threonine and alloisoleucine compared to controls (p < 0.05). The urine organic acids showed significantly elevated excretion of the branched chain ketoacids and succinate (p < 0.05). However there were no biochemical markers that correlated significantly with the neurologic features. CONCLUSION: The findings suggest that there could still be altered LNAA metabolism among patients with MSUD when the BCAAs are elevated. Although the biochemical findings were not significantly correlated with the neurologic features, the study showed that prevention and avoidance of neurologic disturbances may still rely primarily on early diagnosis and prompt institution of treatment, along with strict compliance with the dietary regimen and maintenance of good metabolic control over time.

Biochemical findings in the first Filipino child confirmed to have nonketotic hyperglycinemia: A case report

@#<p style="text-align: justify;">This is a report of the biochemical findings in the first diagnosed case of Nonketotic Hyperglycinemia (NKH) in the Philippines. Urine metabolic screening by high voltage electrophoresis showing grossly increased glycine necessitated  confirmation of NKH. Confirmatory analysis was done by paired plasma-cerebrospinal fluid quantitative amino acid analysis using Ultrahigh Performance Liquid Chromatography (UPLC). The result was compatible with the clinical picture of the patient who presented primarily with apnea, seizures, hypotonia and lethargy. This paper emphasizes the importance of locally available biochemical genetic tests in the diagnosis of inborn errors of metabolism.</p>

The Coffin-Siris syndrome: a proposed diagnostic approach and assessment of 15 overlapping cases.

Coffin-Siris syndrome (CSS) is a rare, clinically heterogeneous disorder often considered in the setting of cognitive/developmental delay and 5th finger/nail hypoplasia. Due to the clinical variability of facial and other features, this diagnosis is often difficult to confirm clinically and the existence of this disorder as a specific diagnosis has been at times an issue of debate. In an effort to further delineate the spectrum and key phenotypic features, we reviewed 80 previously reported cases to define features in patients that most closely correlated with a convincing diagnosis. There appear to be two subtypes of CSS, one which displays the "classic" coarse facial features previously described; another displays "variant" facial features which are less striking. Using these features, we defined an algorithm to rank the confidence of diagnosis and applied it to 15 additional patients who had been previously characterized by chromosome microarray. This approach will also facilitate uniform categorization for whole-exome analysis.

Classical hemocystinuria in two Filipino patients

Classical hemocystinuria is an inborn error of metabolism caused by a deficiency of cystathionine beta-synthase that converts hemocysteine to cystathionine. This then leads to elevation of hemocysteine which results in abnormalities of the eyes, skeleton, central nervous system and vascular hemocystinuria. Patient 1 presented with lens dislocation and mental retardation while Patient 2 presented with thromboembolism, mental retardation and lens dislocation. The elevated plasma hemocysteine and methionine levels lead to the diagnosis of hemocystinuria.

Mitochondrial encephalomyopathy lactic acidosis and stroke-like episodes (MELAS) in a two-year-old Filipino child

MELAS is a mitochondrial respiratory chain disorder characterized by progressive neurodegeneration associated with stroke-like episode, increased plasma lactate levels and distinctive findings on neuroimaging studies. Hence we onset of right-sided hemiplegia accompanied by lactic acidosis and CT-Scan findings of diffuse hypodensity of the cerebral white matter at the time of the stroke-like episode. The diagnosis was confirmed by mutation analysis on blood and hair which showed the typical mtDNA A3243G mutation. This is the first local report of a confirmed case of MELAS.

Clinical profiles of hyperphenylalaninemia patients diagnosed by newborn screening

Hyperphenylalaninemia is due to problems in phenylalanine metabolism caused by defects in phenylalanine hydroxylase enzyme and its co-factor, tetrahydrobiopterin (BH4). This paper presents a review of patients with hyperphenylalaninemia (HPA) diagnosed by Newborn Screening Center-National Institutes of Health from 1996 to 2009. Thirteen cases were diagnosed: five classical phenylketonuria (PKU), one mild PKU, three 6-pyruvoyl tetrahydrobiopterin synthase (6-PTPS) deficiency, and four mild hyperphenylalaninemia (HPA). The clinical profile of the patients highlights the importance of early diagnosis and dietary treatment, good metabolic control and regular monitoring, for better outcome.

Mitochondrial respiratory chain disorder in two Filipino children

Mitochondrial respiratory chain disorders have very diverse manifestations and can present with any symptom, in any organ at any time. Here we describe two Filipino children confirmed to have a mitochondrial respiratory chain disorder after presenting with non-specific neurologic symptoms. The first patient had Otahara syndrome and was later on found to have complex I deficiency. The second patient had the m.8993T>G mtDNA mutation that was consistent with a Leigh phenotype.

Menkes disease mimicking non-accidental injury in a Filipino child

We report an 11-month-old male who presented with recurrent seizures, subdural bleed, skull fracture, lightly pigmented hair, and fair lax skin. Copper and ceruloplasmin levels were low and gross deletion of ATP7A gene was found confirming the diagnosis of Menkes disease. The presence of subdural bleed and skull fracture prompted a referral to the Child Protection Unit to rule out child abuse.

Biochemical and clinical findings in the first two cases of glutaric aciduria type I in the Philippines

We report the first two diagnosed cases of Glutaric Aciduria Type I (GA I) in the Philippines. The diagnosis was confirmed by urinary organic acid analysis by Gas Chromatography-Mass Spectrometry (GC-MS) which showed the characteristic metabolites for GA I. Review of their clinical features showed macrocephaly, developmental delay, seizures, dystonia and choreoathetotic posturing. Cranial CT scan findings were also compatible with previously reported cases. This paper emphasizes the usefulness of locally available biochemical tools in the diagnosis of inborn errors of metabolism as well as the importance of clinical recognition of these disorders.

Ring chromosome 10 in Filipino child: A case report and review of literature

We report a 12-day-old infant who presented with ambiguous genitalia, short stature, low-set ears, stubby nose, patent ductus arteriosus and ventricular septal defect. He was confirmed to have a ring chromosome 10 by cytogenetic analysis. Review of the literature showed that our patient shared common clinical manifestations with previously described cases.

Intravenous pamidronate treatment in Filipino children with moderate to severe osteogenesis imperfecta

Objective. To present preliminary data on the effects of intravenous pamidronate in children with moderate to severe Osteogenesis Imperfecta (OI). Methods. This is a restrospective study wherein a review of medical records and available serial radiographs of children (N=14) with moderate to severe IO started on pamidronate from 2006 to 2010 was done. Results. Two children have IO Type I, 8 have IO Type III and 4 have IO Type IV. At baseline, 2 had normal height, 8 had height less than minus 2SD and the rest with less than minus 1SD. Twelve out of 14 had vertebral compression fractures. Mean age at start of pamidronate was 5.4 years (range 0.5-11 years). First infusion fever in five patients and transient generalized macular rash in one child were noted. Serum calcium and phosphorus levels were normal at baseline and remained stable. Based on parental report, improvement of motor function was noted. In the 10 children who had at least a year of treatment, long bone fractures decreased from mean annualized fracture rate of 2.6 at baseline to 0.9. In patients with vertebral compression fractures, serial radiographs showed improvement of vertebral shape. Conclusion. This preliminary study shows that treatment was generally well tolerated and led to decrease in long bone fractures, improved vertebral shape and improved function.

Genotype-phenotype correlations in Filipino patients with type 3 gaucher disease

Gaucher disease is an inherited glycolipid storage disorder caused by a deficiency of the lysosomal enzyme glucocerebrosidase. Clinical manifestations include hepatosplenomegaly, skeletal abnormalities, anemia and thrombocytopenia. We present here the corresponding genotypes and the genotype-phenotype correlations of 3 Filipino patients. Clinical phenotypes and genotypes were documented by reviewing the charts of 3 Filipino patients with Gaucher disease. Clinical parameters such as liver and spleen sizes, hematologic variables, disease types and response to enzyme replacement therapy were compared. Likewise, quantitative enzyme assays and mutation analysis were reviewed. All have the type III neuronopathic Gaucher disease. Patients 1 and 2 are twin sisters who both have mild mental retardation with Patient 1 having a concomitant seizure disorder. They have the corresponding genotype of p.L444/p.P319A. Patient 3 has global developmental delay, oculomotor apraxia, pyramidal tract signs and carries the p.L444P/p.G202R/p.G202R genotype. Genotype-phenotype correlations for the 3 patients showed that their genotypes are compatible with the severe neuronopathic type of disease.

Mutations of the phenylalanine hydroxylase (PAH) gene in Filipino patients with phenylketonuria

INTRODUCTION: Phenylketonuria (PKU), an autosomal recessive metabolic disorder caused by phenylalanine hydroxylase (PAH) deficiency, leads to hyperphenylalaninemia and neurological damage if untreated. This is the first study in the Philippines to identify the disease-causing mutations in the PAH gene of clinically diagnosed Filipino PKU patients. METHODS: The study included four unrelated PKU patients detected by the Philippine Newborn Screening Program from 1996 to 2008. Plasma amino acid analyses for all patients showed increased phenylalanine and low to normal tyrosine levels consistent with the diagnosis of PKU. Mutations in the PAH gene were identified by genomic DNA extraction from dried blood spots of the patients, PAH exon amplification by polymerase chain reaction and subsequent bi-directional DNA sequence analysis. RESULTS: All patients presented with significantly elevated phenylalanine levels on bacterial inhibition assay and thin layer chromatography. Urinary pterins confirmed the diagnosis of Tetrahydrobiopterin deficiency in two patients while the other 2 patients had the Classical PKU phenotype. Four previously identified mutations in the PAH gene (p.I65T, p.R413P, p.EX6-96A>G, p.R243Q) were identified in those with Classical PKU. CONCLUSION: The present results confirm the heterogeneity of mutations at the PAH locus in Filipinos. Neonatal screening and the use of molecular diagnosis significantly aid in the medical management and genetic counseling of patients and their families.