Slipped Capital Femoral Epiphysis as a Complication of Growth Hormone Therapy

Slipped capital femoral epiphysis (SCFE) is a rare complication of growth hormone (GH) therapy. Here, we report three patients who developed SCFE during GH therapy. The first two patients had hypopituitarism and had started GH therapy at the age of 15 years 6 months and 13 years 9 months, respectively. SCFE developed 4 years and 1 year after GH therapy, respectively. The third patient had Prader-Willi syndrome with obesity and hypogonadism and began GH therapy at the age of 12 years and 11 months. SCFE developed 2 months after starting GH therapy. Pain over the hip joints or over the knees is an early sign of SCFE. Despite recommendation, none of the three patients continued GH therapy. A high index of suspicion during GH therapy in patients at high risk of SCFE is important for early diagnosis and appropriate management. [J Formos Med Assoc 2007;106(2 Suppl):S46-S50

Electrical Abnormalities in Dopaminergic Neurons of the Substantia Nigra in Mice With an Aromatic L-Amino Acid Decarboxylase Deficiency

Aromatic L-acid decarboxylase (AADC) deficiency causes severe motor disturbances in affected children. A putamen-targeted gene therapy improves the motor function of patients. The present study investigated the electrical properties of dopaminergic (DA) neurons in the substantia nigra compacta (SNc) of mice with an AADC deficiency (DdcKI). The basal firing of DA neurons, which determines DA release in the putamen, was abnormal in the DdcKI mice, including a low frequency and irregular firing pattern, because of a decrease in the after-hyperpolarization (AHP) amplitude of action potentials (APs). The frequency of spontaneous excitatory postsynaptic currents (sEPSCs) increased and that of spontaneous inhibitory PSCs (sIPSCs) decreased in the SNc DA neurons from the DdcKI mice, suggesting an elevation in glutamatergic excitatory stimuli and a reduction in GABAergic inhibitory stimuli, respectively. Altered expression patterns of genes encoding receptors and channels were also observed in the DdcKI mice. Administration of a widespread neuron-specific gene therapy to the brains of the DdcKI mice partially corrected these electric abnormalities. The overexcitability of SNc DA neurons in the presence of generalized dopamine deficiency likely underlies the occurrence of motor disturbances

A novel deep intronic variant strongly associates with Alkaptonuria.

Alkaptonuria is a rare autosomal recessive inherited disorder of tyrosine metabolism, which causes ochronosis, arthropathy, cardiac valvular calcification, and urolithiasis. The epidemiology of alkaptonuria in East Asia is not clear. In this study, patients diagnosed with alkaptonuria from January 2010 to June 2020 were reviewed. Their clinical and molecular features were further compared with those of patients from other countries. Three patients were found to have alkaptonuria. Mutation analyses of the homogentisate 1,2-dioxygenase gene (HGD) showed four novel variants c.16-2063 A > C, p.(Thr196Ile), p.(Gly344AspfsTer25), and p.(Gly362Arg) in six mutated alleles (83.3%). RNA sequencing revealed that c.16-2063 A > C activates a cryptic exon, causing protein truncation p.(Tyr5_Ile6insValTer17). A literature search identified another 6 patients with alkaptonuria in East Asia; including our cases, 13 of the 18 mutated alleles have not been reported elsewhere in the world. Alkaptonuria is rare in Taiwan and East Asia, with HGD variants being mostly novel and private

Rapid Trio Exome Sequencing for Autosomal Recessive Renal Tubular Dysgenesis in Recurrent Oligohydramnios

Oligohydramnios is not a rare prenatal finding. However, recurrent oligohydramnios is uncommon, and genetic etiology should be taken into consideration. We present two families with recurrent fetal oligohydramnios that did not respond to amnioinfusion. Rapid trio-whole-exome sequencing (WES) revealed mutations in the AGT gene in both families within 1 week. The first family had a compound heterozygous mutation with c.856 + 1G > T and c.857-619_1269 + 243delinsTTGCCTTGC changes. The second family had homozygous c.857-619_1269 + 243delinsTTGCCTTGC mutations. AGT gene mutation may lead to autosomal recessive renal tubular dysgenesis, a rare and lethal disorder that can result in early neonatal death. Both the alleles identified are known alleles associated with pathogenicity. Our findings suggest that trio-WES analysis may help rapidly identify causative etiologies that can inform prompt counseling and decision-making prenatally

Results of Fabry Disease Screening in Male Pre-End Stage Renal Disease Patients with Unknown Etiology Found Through the Platform of a Chronic Kidney Disease Education Program in a Northern Taiwan Medical Center

Background/Aims: Fabry disease (FD), a rare x-lined genetic disorder is a cause of renal deterioration. The phenotype of FD is highly variable and nonspecific, and correct diagnosis has always been delayed. We aimed to explore the prevalence and clinical presentation of FD in this high-risk male population in a Northern Taiwan medical center. Methods: This is the first study to survey the incidence of FD in this high-risk population through the platform of a chronic kidney disease (CKD) education program in Asia. A total of 1,012 male patients with unknown CKD causes were screened using an assay of alpha-galactosidase A activity (α-Gal A) by dried blood spots (DBS). A final GLA gene analysis was also done for those with low enzyme activity. Results: We identified two new patients with classic FD and four patients with late-onset FD. One novel GLA mutation with c.413 G>A was found in one classic FD patient (index 5). The prevalence of FD is about 0.59 % (6 in 1,012) in the high-risk population group with CKD. The clinical symptoms of FD patients are nonspecific except in those with various degrees of renal failure. Those patients’ correct diagnosis was delayed, taking years and even decades. Three patients received enzyme replacement therapy and one started regular hemodialysis due to persistent renal function deterioration. Another two patients were found from family screening through a new index. In addition, a false negative result occurred in one patient who was proved to have FD by his kidney pathology as determined by this screening. Conclusion: FD is not such as rare a disease and its prevalence is greater in this high-risk male population. Clinicians need to be aware that FD should be included in the differential diagnosis in CKD with unknown etiology

Natural history of perinatal and infantile hypophosphatasia: A retrospective study

Objective: To report clinical characteristics and medical history data obtained retrospectively for a large cohort of pediatric patients with perinatal and infantile hypophosphatasia. Study design: Medical records from academic medical centers known to diagnose and/or treat hypophosphatasia were reviewed. Patients born between 1970 and 2011 with hypophosphatasia and any of the following signs/symptoms at age <6 months were eligible: vitamin B6–dependent seizures, respiratory compromise, or rachitic chest deformity (NCT01419028). Patient demographics and characteristics, respiratory support requirements, invasive ventilator–free survival, and further complications of hypophosphatasia were followed for up to the first 5 years of life. Results: Forty-eight patients represented 12 study sites in 7 countries; 13 patients were alive, and 35 were dead (including 1 stillborn). Chest deformity, respiratory distress, respiratory failure (as conditioned by the eligibility criteria), failure to thrive, and elevated calcium levels were present in >70% of patients between birth and age 5 years. Vitamin B6–dependent seizures and respiratory distress and failure were associated significantly (P <.05)with the risk of early death. Serum alkaline phosphatase activity in all 41 patients tested (mean [SD]: 18.1 [15.4]U/L)was below the mean lower limit of normal of the reference ranges of the various laboratories (88.2 U/L). Among the 45 patients with relevant data, 29 had received respiratory support, of whom 26 had died at the time of data collection. The likelihood of invasive ventilator–free survival for this cohort decreased to 63% at 3 months, 54% at 6 months, 31% at 12 months, and 25% at 5 years. Conclusions: Patients with perinatal or infantile hypophosphatasia and vitamin B6–dependent seizures, with or without significant respiratory distress or chest deformities, have high morbidity and mortality in the first 5 years of life. Trial registration: ClinicalTrials.gov: NCT01419028

Type I Gaucher disease with exophthalmos and pulmonary arteriovenous malformation

BACKGROUND: Gaucher disease type I, the non-neuropathic type, usually presents in adulthood with hepatosplenomegaly. We report here an adult with type I Gaucher disease presented with unusual and severe clinical manifestations. CASE PRESENTATION: Hepatosplenomegaly, bone crisis and fractures occurred at early childhood, and splenectomy was performed at the age of 5. Exophthalmos with increase in retrobulbar space was noted when the patient was 30. Cerezyme infusion started at the age of 32; but unfortunately, pulmonary arteriovenous malformation with dyspnea and hypoxemia was found two years later. Gene analysis revealed V375L/L444P mutations in the β-glucocerebrosidase gene. CONCLUSION: Although both eye and lung diseases have been associated with Gaucher disease, this is the first reported demonstration of exophthalmos and pulmonary arteriovenous malformation in the same patient. This case may therefore present an extremely severe and unusual form of type I Gaucher disease

Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic

Genome-Wide Gene Expression Analysis Implicates the Immune Response and Lymphangiogenesis in the Pathogenesis of Fetal Chylothorax

Fetal chylothorax (FC) is a rare condition characterized by lymphocyte-rich pleural effusion. Although its pathogenesis remains elusive, it may involve inflammation, since there are increased concentrations of proinflammatory mediators in pleural fluids. Only a few hereditary lymphedema-associated gene loci, e.g. VEGFR3, ITGA9 and PTPN11, were detected in human fetuses with this condition; these cases had a poorer prognosis, due to defective lymphangiogenesis. In the present study, genome-wide gene expression analysis was conducted, comparing pleural and ascitic fluids in three hydropic fetuses, one with and two without the ITGA9 mutation. One fetus (the index case), from a dizygotic pregnancy (the cotwin was unaffected), received antenatal OK-432 pleurodesis and survived beyond the neonatal stage, despite having the ITGA9 mutation. Genes and pathways involved in the immune response were universally up-regulated in fetal pleural fluids compared to those in ascitic fluids. Furthermore, genes involved in the lymphangiogenesis pathway were down-regulated in fetal pleural fluids (compared to ascitic fluid), but following OK-432 pleurodesis, they were up-regulated. Expression of ITGA9 was concordant with overall trends of lymphangiogenesis. In conclusion, we inferred that both the immune response and lymphangiogenesis were implicated in the pathogenesis of fetal chylothorax. Furthermore, genome-wide gene expression microarray analysis may facilitate personalized medicine by selecting the most appropriate treatment, according to the specific circumstances of the patient, for this rare, but heterogeneous disease

Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes

Aromatic L-amino acid decarboxylase (AADC) deficiency is a rare autosomal recessive genetic disorder affecting the biosynthesis of dopamine, a precursor of both norepinephrine and epinephrine, and serotonin. Diagnosis is based on the analysis of CSF or plasma metabolites, AADC activity in plasma and genetic testing for variants in the DDC gene. The exact prevalence of AADC deficiency, the number of patients, and the variant and genotype prevalence are not known. Here, we present the DDC variant (n = 143) and genotype (n = 151) prevalence of 348 patients with AADC deficiency, 121 of whom were previously not reported. In addition, we report 26 new DDC variants, classify them according to the ACMG/AMP/ACGS recommendations for pathogenicity and score them based on the predicted structural effect. The splice variant c.714+4A>T, with a founder effect in Taiwan and China, was the most common variant (allele frequency = 32.4%), and c.[714+4A>T];[714+4A>T] was the most common genotype (genotype frequency = 21.3%). Approximately 90% of genotypes had variants classified as pathogenic or likely pathogenic, while 7% had one VUS allele and 3% had two VUS alleles. Only one benign variant was reported. Homozygous and compound heterozygous genotypes were interpreted in terms of AADC protein and categorized as: i) devoid of full-length AADC, ii) bearing one type of AADC homodimeric variant or iii) producing an AADC protein population composed of two homodimeric and one heterodimeric variant. Based on structural features, a score was attributed for all homodimers, and a tentative prediction was advanced for the heterodimer. Almost all AADC protein variants were pathogenic or likely pathogenic