Clinical manifestations

Presentation and course

Clinical manifestations in aminoacylase 1 deficiency vary widely, from muscular hypotonia and normal psychomotor development to brain malformations and intellectual disability (25; 28; 02). Most individuals with aminoacylase 1 deficiency exhibit neurologic symptoms, such as epileptic seizures (31; 24; 25; 08; 19). Similar to that of other organic acidurias, seizures have occurred during episodes of illness in the neonatal period or in later childhood (31; 25). Autism-like features have also been noted in aminoacylase 1 deficiency (30). A 63-year-old woman with generalized dystonia and aminoacylase 1 deficiency has been reported (26). Based solely on urinary metabolites, aminoacylase 1 deficiency was considered in the differential diagnosis of a girl with glutaric aciduria type 3 with episodes of cycling vomiting (32). Another patient showed a simultaneous presence of genetically confirmed Menkes disease and aminoacylase deficiency (15).

Prognosis and complications

Due to the young age of most ACY1-deficient individuals, the clinical course and natural history of the disorder cannot be reliably predicted.

Clinical vignette

Given the wide range of clinical presentations in the small number of patients reported so far, a clinical vignette would likely be misleading. The unifying feature of all individuals with aminoacylase 1 deficiency is the elevated concentrations of urinary acylated amino acids, including N-acetylmethionine, N-acetylglutamic acid, and N-acetylated derivatives of alanine, leucine, glycine, valine, and isoleucine, without an increase in N-acetylaspartate. These metabolites can be identified by gas chromatography with mass-selective detection (urinary organic acids) or by in vitro nuclear magnetic resonance spectrometry (24; 07).

Biological basis

Etiology and pathogenesis

The expression of aminoacylase 1 in the human brain is compatible with the enzyme’s role in the central nervous system (17; 24). The young age of most ACY1-deficient individuals described may be because the clinical course cannot be fully predicted and the natural history of aminoacylase 1 deficiency is uncertain. ACY1 can contribute to the inhibition of apoptosis and is one of a few proteins that exhibit altered expression in mouse models for Huntington disease and fragile X syndrome (14; 34). Thus, ACY1 may represent a predisposing factor or modifier later in life, affecting severity, or is a manifestation of various neurologic diseases. This could explain the phenotypic variability reported in ACY1-deficient individuals, but long-term follow-up studies with a larger number of affected individuals are needed. Notably, two large studies have drawn attention to the association of aminoacylase 1 and type 2 diabetes (06; 22).

The expression of ACY1 in the kidney of normal individuals may explain the elevated concentrations of N-acetylated amino acids in the urine of ACY1-deficient individuals (13; 24). Possibly, in the case of severe dietary protein restriction, ACY1 dysfunction contributes to reduced availability of amino acids due to impaired amino acid salvage, rendering aminoacylase 1 deficiency a disadvantage during periods of profound catabolism or starvation. Because ACY1 can also catalyze acylation reactions, such as the synthesis of hippuric acid from glycine and benzoic acid, Lindner and colleagues have suggested that benzoylglycine (hippuric acid) synthesis, catalyzed by ACY1, is a cytosolic benzoate detoxification pathway in addition to being involved in mitochondrial glycine conjugation (27; 13). Thus, ACY1-dependent detoxification of benzoic acid may have been advantageous before the transition of humans from herbivores to omnivores and may be beneficial in vegetarians. Consequences of aminoacylase 1 deficiency may also result from a role in drug metabolism. For example, aminoacylase activity is involved in the metabolism of mercapturates, which are formed from drugs, such as paracetamol (01). The concentration of serum ACY1 has been suggested as a prognostic biomarker for long-term outcome in individuals with delayed graft function following renal transplantation (33). ACY1 has been reported as a blood-based biomarker in Parkinson disease (23). Lai and colleagues have ascribed a key role for ACY1 in causing myocardial fibrosis (11).

Genetics. Aminoacylase 1 deficiency is an autosomal recessively inherited disorder caused by mutations in the ACY1 gene on human chromosome 3 (24).

Epidemiology

ACY1 deficiency may be a panethnic inborn error of metabolism. However, the small number of affected individuals known so far does not allow substantial conclusions regarding epidemiology.

Prevention

This genetic disorder cannot be prevented.

Differential diagnosis

Confusing conditions

A deficiency of aspartoacylase (ACY2) results in Canavan disease, which is characterized by isolated elevation of N-acetylaspartic acid in body fluids (12). In contrast, there is no increase in N-acetylaspartic acid concentrations in aminoacylase 1 deficiency, but there are elevated concentrations of other N-acetylated derivatives of amino acids (eg, methionine, glutamic acid, alanine, leucine, glycine, valine, and isoleucine) (24; 07). In maple syrup urine disease, elevated concentrations of N-acetylated branched-chain amino acids may be found but not abnormal concentrations of N-acetylmethionine, N-acetylglutamic acid, etc. (09). In hypertyrosinemia or phenylketonuria or following parenteral administration of N-acetyltyrosine, only increases in urinary N-acetyltyrosine or N-phenylalanine are found (09).

Diagnostic workup

Urinary organic acid analysis may indicate metabolites consistent with aminoacylase 1 deficiency together with clinical symptoms of familial anamnesis. Aminoacylase 1 deficiency can be confirmed by enzymatic activity assay or mutation analysis of the ACY1 gene (24).

Diagnostic ACY1 enzymatic activity can be determined in EBV-transformed lymphocytes prepared from peripheral blood or in cultivated fibroblasts (25). Expression analyses in HEK293 cells of human mutations in the ACY1 gene have been reported (28).

Management

Based on the current information, treatment of individuals with aminoacylase 1 deficiency is symptomatic. General management advice is not available because aminoacylase 1 deficiency has not been proven to cause clinical features.

Special considerations

Pregnancy

Pregnancy in a woman with aminoacylase 1 deficiency has not been reported.