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.

Identifying the need for a multidisciplinary approach for early recognition of mucopolysaccharidosis VI (MPS VI).

Mucopolysaccharidosis VI (MPS VI, Maroteaux-Lamy syndrome) is caused by deficient activity of the enzyme, N-acetylgalactosamine-4-sulfatase, resulting in impaired degradation of the glycosaminoglycan dermatan sulfate. Patients experience a range of manifestations including joint contractures, short stature, dysostosis multiplex, coarse facial features, decreased pulmonary function, cardiac abnormalities, corneal clouding and shortened life span. Recently, clinicians from institutions in the Asia-Pacific region met to discuss the occurrence and implications of delayed diagnosis and misdiagnosis of MPS VI in the patients they have managed. Eighteen patients (44% female) were diagnosed. The most common sign presented by the patients was bone deformities in 11 patients (65%). Delays to diagnosis occurred due to the lack of or distance to diagnostic facilities for four patients (31%), alternative diagnoses for two patients (15%), and misleading symptoms experienced by two patients (15%). Several patients experienced manifestations that were subtler than would be expected and were subsequently overlooked. Several cases highlighted the unique challenges associated with diagnosing MPS VI from the perspective of different specialties and provide insights into how these patients initially present, which may help to elucidate strategies to improve the diagnosis of MPS VI.

Pilot study of newborn screening of inborn error of metabolism using tandem mass spectrometry in Malaysia: outcome and challenges.

BACKGROUND: The aim of this study was to determine the feasibility of performing newborn screening (NBS) of inborn errors of metabolism (IEMs) using tandem mass spectrometry (TMS) and the impact on its detection rate in Malaysia. METHODS: During the study period between June 2006 and December 2008, 30,247 newborns from 11 major public hospitals in Malaysia were screened for 27 inborn errors of amino acid, organic acid and fatty acid metabolism by TMS. Dried blood spot (DBS) samples were collected between 24 h and 7 days with parental consent. Samples with abnormal results were repeated and the babies were recalled to confirm the diagnosis with follow-up testing. RESULTS: Cut-off values for amino acids and acylcarnitines were established. Eight newborns were confirmed to have IEM: two newborns with Maple syrup urine disease (MSUD), two with methylmalonic aciduria (MMA) one with ethylmalonic aciduria, two with argininosuccinic aciduria and one with isovaleric aciduria. Diagnosis was missed in two newborns. The detection rate of IEMs in this study was one in 2916 newborns. The sensitivity and specificity of TMS were 80% and 99%, respectively. CONCLUSIONS: IEMs are common in Malaysia. NBS of IEMs by TMS is a valuable preventive strategy by enabling the diagnosis and early treatment of IEM before the onset of symptoms aiming at prevention of mental retardation and physical handicap. A number of shortcomings warrant further solution so that in near future NBS for IEMs will become a standard of care for all babies in Malaysia in tandem with the developed world.

Overcoming the barriers to diagnosis of Morquio A syndrome.

BACKGROUND: Morquio A syndrome is an autosomal recessive lysosomal storage disease often resulting in life-threatening complications. Early recognition and proficient diagnosis is imperative to facilitate prompt treatment and prevention of clinical complications. METHODS: Experts in Asia Pacific reviewed medical records focusing on presenting signs and symptoms leading to a diagnosis of Morquio A syndrome. RESULTS: Eighteen patients (77% female) had a mean (median; min, max) age of 77.1 (42.0; 0.0, 540.0) months at symptom onset, 78.9 (42.0; 4.5, 540.0) months at presentation and 113.8 (60.0; 7.0, 540.0) months at diagnosis. Orthopedic surgeons and pediatricians were most frequently consulted pre-diagnosis while clinical geneticists/metabolic specialists most frequently made the diagnosis. Delayed diagnoses were due to atypical symptoms for 5 patients (28%), while 4 patients (22%) experienced each of subtle symptoms, symptoms commonly associated with other diseases, or false-negative urine glycosaminoglycan analysis. Two patients (11%) each experienced overgrowth within the first year of life. Two patients with Morquio A syndrome (11%) were diagnosed with craniosynostosis and 1 (6%) for each of Legg-Calvé-Perthes disease, Leri-Weill syndrome, and pseudoachondroplasia. Early radiographic features of Morquio A syndrome led to more efficient diagnosis. CONCLUSIONS: Increased awareness of clinical symptomology overlapping with Morquio A syndrome is essential. Clinicians encountering patients with certain skeletal dysplasia should consider Morquio A syndrome in their differential diagnosis. Atypical or subtle symptoms should not eliminate Morquio A syndrome from the differential diagnosis, especially for patients who may have non-classical phenotype of Morquio A syndrome.