Aminoacylase 1 Deficiency

A number sign (#) is used with this entry because aminoacylase-1 deficiency (ACY1D) is caused by homozygous or compound heterozygous mutation in the ACY1 gene (104620) on chromosome 3p21.

Description

Aminoacylase-1 deficiency (ACY1D) is a rare autosomal recessive inborn error of metabolism characterized by increased urinary excretion of specific N-actyl amino acids. Most patients show neurologic abnormalities such as intellectual disability, seizures, hypotonia, and motor delay (summary by Ferri et al., 2014).

Clinical Features

Van Coster et al. (2005) reported an infant with aminoacylase-1 deficiency. He presented neonatally with an acute encephalopathy with onset on the third day of life and duration of about 2 weeks. Clinical features included seizures, apnea, vomiting, hypotonia, and sensorineural hearing loss. Urinalysis detected several N-acetylated amino acids. MRI showed cerebral atrophy. At age 9 months, he had reached normal developmental milestones and there were no abnormal clinical neurologic signs.

Sass et al. (2006) reported 4 children with a genetic deficiency of ACY1. They were identified through organic acid analyses using gas chromatography-mass spectrometry, revealing increased urinary secretion of several N-acetylated amino acids, including the derivatives of methionine, glutamic acid, alanine, leucine, glycine, valine, and isoleucine. Nuclear magnetic resonance spectroscopy analysis of urine samples detected a distinct pattern of N-acetylated metabolites, consistent with ACY1 dysfunction. Functional analyses of patients' lymphoblasts demonstrated ACY1 deficiency. The clinical phenotypes of the patients were heterogeneous: nonspecific psychomotor delay in 1 subject, psychomotor delay with atrophy of the vermis and syringomyelia in a second, marked muscular hypotonia in a third, and follow-up for early treated biotinidase deficiency with normal clinical findings in the fourth. The organic acids analysis that led to the detection of ACY1 deficiency was part of selective screening for inborn errors of metabolism, which is not performed routinely in healthy children but only in individuals in whom a metabolic disease is considered, resulting in a strong bias. It was uncertain whether ACY1 deficiency had pathogenic significance with pleiotropic clinical expression or was simply a biochemical variant. Sass et al. (2006) noted that the phenotypic variability of the patients did not support ACY1 deficiency as a disease. However, evolutionarily conservation of the ACY1 gene in fish, frog, mouse, and human, and its expression in the central nervous system in human, suggested a role of the enzyme in the amino acid metabolism of these organs. ACY1 is expressed in the kidney, an observation in line with a possible functional role of ACY1 in recycling of N-acetylated amino acids in the kidney, which could explain the highly elevated concentrations of N-acetylated amino acids in the urine of the 4 children harboring ACY1 mutations. Thus, in the case of severe dietary protein restriction, ACY1 dysfunction might contribute to reduced availability of amino acids due to impaired amino acid salvage. This could be a disadvantage during periods of profound catabolism or starvation. In addition, ACY1 deficiency might result in accumulation of acetylated amino acids in analogy to N-acetylaspartic acid in aminoacylase-2 (ACY2) deficiency (Canavan disease; 271900). A role of ACY1 in detoxification of benzoic acid and in the metabolism of certain drugs was suggested by Sass et al. (2006), who also suggested that ACY1 deficiency might have consequences later in life, perhaps as a predisposing factor or modifier.

Sass et al. (2007) reported 3 additional patients with ACY1 deficiency detected through newborn screening. Two patients were born of consanguineous parents of Asian and Romani origin, respectively. The Asian child presented with febrile seizures at 11 months of age, followed 3 months later by more seizures associated with a viral illness. She showed delayed speech and language development at age 4 years. The Romani child had onset of multifocal, drug-resistant epilepsy with atonic, tonic, and absence seizures at age 1 year. He was hyperactive with moderate mental retardation. He also had a broad nasal root and hypertelorism. The third patient, of English origin, presented at age 11 months with a prolonged generalized seizure and transient hemiplegia associated with illness. She showed complete recovery and normal development at age 19 months.

Ferri et al. (2014) reported a 6-year-old girl, born of consanguineous parents, with severe neurologic manifestations associated with ACY1 deficiency. She first presented at age 3 years with an episode of severe opisthotonos. She had a complex nonspecific neurologic phenotype including severe intellectual disability, axial hypotonia with inability to walk, limb hypertonia, and severe speech delay. Brain MRI showed dilatation of the left temporal horn. Urinary organic acid analysis showed increased levels of N-acetyl amino acids, consistent with a diagnosis of ACY1 deficiency.

Inheritance

The transmission pattern of ACY1 deficiency in the families reported by Sass et al. (2007) and Ferri et al. (2014) was consistent with autosomal recessive inheritance.

Molecular Genetics

In an infant with ACY1 deficiency, Van Coster et al. (2005) identified a homozygous mutation in the ACY1 gene (R353C; 104620.0002) resulting in loss of enzyme activity.

In 4 children with ACY1 deficiency, Sass et al. (2006) identified homozygous loss-of-function or missense mutations in the ACY1 gene. Segregation analyses revealed that all parents studied were heterozygous carriers of the mutations. The R353C mutation that was found in 2 of the 4 affected individuals was also found in 1 of 210 control chromosomes, consistent with the variant being a rare polymorphism or a more common mutation.

Sass et al. (2007) identified compound heterozygous or homozygous mutations in the ACY1 gene (104620.0002; 104620.0005; 104620.0006) in 3 unrelated patients with ACY1 deficiency. R353C was the most common mutation, present in 3 of the 6 alleles.

In a 6-year-old girl, born of consanguineous parents, with severe neurologic impairment associated with ACY1 deficiency, Ferri et al. (2014) identified a homozygous truncating mutation in the ACY1 gene (104620.0007). Patient fibroblasts showed complete absence of ACY1 enzyme activity.