Refine
Department, Institute
Keywords
- 5-Oxoprolinase (1)
- 5-oxoprolinuria (1)
- AMT (1)
- Epilepsy (1)
- GLYCTK (1)
- Glutathione synthetase (1)
- Inborn errors of metabolism (1)
- Nonketotic hyperglycinemia (1)
- Pyroglutamic aciduria (1)
- d-Glycerate kinase deficiency (1)
3-hydroxyisobutyric aciduria is an organic aciduria with a poorly understood biochemical basis. It has previously been assumed that deficiency of 3-hydroxyisobutyrate dehydrogenase (HIBADH) in the valine catabolic pathway is the underlying enzyme defect, but more recent evidence makes it likely that individuals with 3-hydroxyisobutyryic aciduria represent a heterogeneous group with different underlying mechanisms, including respiratory chain defects or deficiency of methylmalonate semialdehyde dehydrogenase. However, to date methylmalonate semialdehyde dehydrogenase deficiency has only been demonstrated at the gene level for a single individual. We present two unrelated patients who presented with developmental delay and increased urinary concentrations of 3-hydroxyisobutyric acid. Both children were products of consanguineous unions and were of European or Pakistani descent. One patient developed a febrile illness and subsequently died from a hepatoencephalopathy at 2 years of age. Further studies were initiated and included tests of the HIBADH enzyme in fibroblast homogenates, which yielded normal activities. Sequencing of the ALDH6A1 gene (encoding methylmalonate semialdehyde dehydrogenase) suggested homozygosity for the missense mutation c.785 C > A (S262Y) in exon 7 which was not found in 210 control alleles. Mutation analysis of the ALDH6A1 gene of the second patient confirmed the presence of a different missense mutation, c.184 C > T (P62S), which was also identified in 1/530 control chromosomes. Both mutations affect highly evolutionarily conserved amino acids of the methylmalonate semialdehyde dehydrogenase protein. Mutation analysis in the ALDH6A1 gene can reveal a cause of 3-hydroxyisobutyric aciduria, which may present with only slightly increased urinary levels of 3-hydroxyisobutyric acid, if a patient is metabolically stable.
Aminoacylase 1 (ACY1) deficiency is a recently described inborn error of metabolism. Most of the patients reported so far have presented with rather heterogeneous neurologic symptoms. At this moment, it is not clear whether ACY1 deficiency represents a true metabolic disease with a causal relationship between the enzyme defect and the clinical phenotype or merely a biochemical abnormality. Here we present a patient identified in the course of selective screening for inborn errors of metabolism (IEM). The patient was diagnosed with autistic syndrome and admitted to the Children's Memorial Health Institute (CMHI) for metabolic evaluation. Organic acid analysis using gas chromatography-mass spectrometry (GC-MS) revealed increased urinary excretion of several N-acetylated amino acids, including the derivatives of methionine, glutamic acid, alanine, glycine, leucine, isoleucine, and valine. In Epstein-Barr virus (EBV)-transformed lymphoblasts, ACY1 activity was deficient. The mutation analysis showed a homozygous c.1057C>T transition, predicting a p.Arg353Cys substitution. Both parents were heterozygous for the mutation and had normal results in the organic acid analysis using GC-MS. This article reports the findings of an ACY1-deficient patient presenting with autistic features.
BACKGROUND
Propionic acidemia is an inherited disorder caused by deficiency of propionyl-CoA carboxylase. Although it is one of the most frequent organic acidurias, information on the outcome of affected individuals is still limited.
STUDY DESIGN/METHODS
Clinical and outcome data of 55 patients with propionic acidemia from 16 European metabolic centers were evaluated retrospectively. 35 patients were diagnosed by selective metabolic screening while 20 patients were identified by newborn screening. Endocrine parameters and bone age were evaluated. In addition, IQ testing was performed and the patients' and their families' quality of life was assessed.
RESULTS
The vast majority of patients (>85%) presented with metabolic decompensation in the neonatal period. Asymptomatic individuals were the exception. About three quarters of the study population was mentally retarded, median IQ was 55. Apart from neurologic symptoms, complications comprised hematologic abnormalities, cardiac diseases, feeding problems and impaired growth. Most patients considered their quality of life high. However, according to the parents' point of view psychic problems were four times more common in propionic acidemia patients than in healthy controls.
CONCLUSION
Our data show that the outcome of propionic acidemia is still unfavourable, in spite of improved clinical management. Many patients develop long-term complications affecting different organ systems. Impairment of neurocognitive development is of special concern. Nevertheless, self-assessment of quality of life of the patients and their parents yielded rather positive results.
