4 research outputs found
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
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
Assessment of intellectual impairment, health-related quality of life, and behavioral phenotype in patients with neurotransmitter related disorders: Data from the iNTD registry
Inherited disorders of neurotransmitter metabolism are a group of rare
diseases, which are caused by impaired synthesis, transport, or
degradation of neurotransmitters or cofactors and result in various
degrees of delayed or impaired psychomotor development. To assess the
effect of neurotransmitter deficiencies on intelligence, quality of
life, and behavior, the data of 148 patients in the registry of the
International Working Group on Neurotransmitter Related Disorders (iNTD)
was evaluated using results from standardized age-adjusted tests and
questionnaires. Patients with a primary disorder of monoamine metabolism
had lower IQ scores (mean IQ 58, range 40-100) within the range of
cognitive impairment (<70) compared to patients with a BH4 deficiency
(mean IQ 84, range 40-129). Short attention span and distractibility
were most frequently mentioned by parents, while patients reported most
frequently anxiety and distractibility when asked for behavioral traits.
In individuals with succinic semialdehyde dehydrogenase deficiency,
self-stimulatory behaviors were commonly reported by parents, whereas in
patients with dopamine transporter deficiency, DNAJC12 deficiency, and
monoamine oxidase A deficiency, self-injurious or mutilating behaviors
have commonly been observed. Phobic fears were increased in patients
with 6-pyruvoyltetrahydropterin synthase deficiency, while individuals
with sepiapterin reductase deficiency frequently experienced
communication and sleep difficulties. Patients with BH4 deficiencies
achieved significantly higher quality of life as compared to other
groups. This analysis of the iNTD registry data highlights: (a)
difference in IQ and subdomains of quality of life between BH4
deficiencies and primary neurotransmitter-related disorders and (b)
previously underreported behavioral traits
Corrigendum to:Prevalence of DDC genotypes in patients with aromatic L-amino acid decarboxylase (AADC) deficiency and in silico prediction of structural protein changes (Molecular Genetics and Metabolism (2023) 139(3), (S1096719223002548), (10.1016/j.ymgme.2023.107624))
The authors regret that the printed version of the above article contained an incomplete list of references, particularly those listed in the Table 1. The changes do not affect the main conclusion of this article. The authors would like to apologize for any inconvenience caused.</p