Aminoacylase 1 Deficiency

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Classifications

ICIMD (Inherited Metabolic Disorders)

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Inheritance

1

Autosomal recessive HP:0000007

Autosomal recessive inheritance

Show evidence (1 reference)

PMID:21414403 SUPPORT Human Clinical

"follows an autosomal-recessive trait of inheritance"

States that aminoacylase 1 deficiency is inherited in an autosomal recessive manner.

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Mechanistic Hypotheses

2

N-acetylated amino-acid mitochondrial bioenergetic toxicity

n_acetyl_mitochondrial_bioenergetic_hypothesis EMERGING

Evidence balance 1 support

Accumulating N-acetylglutamate and N-acetylmethionine may impair neuronal mitochondrial respiratory-chain and glutamate-dehydrogenase activities and reduce ATP synthesis, providing a candidate link from the biochemical defect to neurological findings. The evidence is limited to in-vitro exposure of developing-rat brain mitochondrial preparations; human CSF accumulation was not detected in the one patient tested.

Pathograph links

Accumulation and Urinary Excretion of N-Acetylated Amino Acids -> Mitochondrial Brain Energy Impairment DIRECT N-acetylglutamate and N-acetylmethionine directly impaired mitochondrial enzymes and ATP synthesis in vitro.

Mitochondrial Brain Energy Impairment -> Heterogeneous Neurological Manifestations of Uncertain Causality INDIRECT UNKNOWN INTERMEDIATES Mitochondrial energy impairment could contribute to neurological findings, but this has not been shown in affected humans.

Show evidence (1 reference)

PMID:37871522 SUPPORT In Vitro

"Finally, NAG and NAM strongly decreased mitochondrial ATP synthesis."

Directly supports mitochondrial ATP impairment in the experimental preparation, but not in human brain.

ACY1-dependent auditory hair-cell development

acy1_auditory_hair_cell_hypothesis EMERGING

Evidence balance 2 support

ACY1 loss may impair auditory hair-cell development and function. This model is supported by a single human candidate case and by morpholino knockdown and rescue in zebrafish, but the gene-hearing-loss relationship requires unrelated human cases and independent replication.

Pathograph links

Aminoacylase 1 Enzyme Deficiency -> Auditory Hair-Cell Developmental Impairment DIRECT ACY1 knockdown reduced zebrafish auditory hair cells and function, with wild-type but not mutant human-mRNA rescue.

Auditory Hair-Cell Developmental Impairment -> Congenital sensorineural hearing impairment INDIRECT UNKNOWN INTERMEDIATES Reduced auditory hair-cell number and function is a candidate mechanism for the single reported human hearing phenotype.

Show evidence (2 references)

PMID:42322530 SUPPORT Model Organism

"A zebrafish model with morpholino-mediated acy1 knockdown revealed a significant reduction in hair cells and impaired auditory function, which were effectively rescued by wild-type but not mutant human ACY1 mRNA."

In-vivo knockdown and allele-specific rescue support the candidate auditory mechanism, with morpholino and cross-species limitations.

PMID:42322530 SUPPORT Human Clinical

"a homozygous splicing variant, c.1063-1G>A, in ACY1 as a plausible candidate variant in a 5-year-old girl with congenital hearing loss and normal developmental milestones over a 4-year follow-up"

Supplies the single human observation while retaining the authors' candidate-level wording.

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Discussions and Knowledge Gaps

3

Is aminoacylase 1 deficiency a true metabolic disease that causally produces its reported neurological phenotypes (psychomotor delay, hypotonia, febrile seizures, intellectual disability, autism, dystonia), or is the enzyme defect largely a benign biochemical variant whose clinical associations reflect ascertainment bias from urine metabolic screening?

KNOWLEDGE GAP OPEN gap_acy1_clinical_significance

Attached to

pathophysiology#Heterogeneous Neurological Manifestations of Uncertain Causality pathophysiology#Accumulation and Urinary Excretion of N-Acetylated Amino Acids

The enzymatic and biochemical basis of aminoacylase 1 deficiency is well established: biallelic ACY1 loss-of-function variants abolish hydrolysis of N-acetyl amino acids and produce a specific urinary N-acetylated amino acid profile. What remains unresolved is the causal link between this defect and clinical disease. Most affected individuals were ascertained through urine metabolic screening rather than a defining clinical phenotype, the reported neurological findings are heterogeneous and nonspecific, one original subject had normal clinical findings, one report found no increase of N-acetylated amino acids in cerebrospinal fluid, and at least one affected adult was cognitively normal. The authors of the defining studies explicitly could not state whether ACY1 deficiency has pathogenic significance with pleiotropic clinical expression or is simply a biochemical variant. Resolving this bears directly on genetic counseling, newborn/metabolic screening interpretation, and whether the condition should be treated as a disease.

Proposed experiments

Ascertainment-unbiased penetrance of ACY1 biallelic loss of function

exp_acy1_unbiased_cohort_penetrance

Estimate the neurodevelopmental phenotype rate among individuals with biallelic ACY1 loss-of-function genotypes identified in large, phenotype-agnostic sequencing biobanks (rather than metabolic-screening cohorts), comparing against matched controls to test whether the genotype is associated with neurological disease independent of ascertainment bias.

CNS consequences of ACY1 loss in a neural model system

exp_acy1_cns_model

Use ACY1-null human iPSC-derived neurons/organoids and/or an animal model to test whether loss of aminoacylase 1 perturbs neuronal metabolism, development, or function, given that ACY1 is expressed in the CNS but no accumulation of N-acetylated amino acids was detected in patient CSF.

Show evidence (2 references)

PMID:20480396 SUPPORT Human Clinical

"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"

The clinical-significance uncertainty is stated directly by the case-report authors.

PMID:38234346 SUPPORT Human Clinical

"Its clinical manifestations are highly variable, ranging from severe neurological symptoms to being asymptomatic."

Recent case literature confirms that clinical variability and asymptomatic disease remain central limitations.

Do N-acetylglutamate and N-acetylmethionine reach concentrations in human brain that impair mitochondrial energy metabolism, as they do in exposed developing-rat brain mitochondrial preparations?

HUMAN MODEL MISMATCH OPEN gap_acy1_mitochondrial_model_translation

Attached to

pathophysiology#Mitochondrial Brain Energy Impairment pathophysiology#Accumulation and Urinary Excretion of N-Acetylated Amino Acids

Experimental evidence now identifies a plausible bioenergetic mechanism, but the preparation was outside an intact organism and did not establish metabolite exposure in human brain. The only reported patient CSF measurement found no increased N-acetylated amino acids, so translating the experimental effect to human neurological disease requires exposure and target-engagement evidence.

Proposed experiments

Human CNS exposure-response validation

exp_acy1_human_cns_exposure_response

Quantify N-acetylated amino acids in paired plasma and CSF from molecularly confirmed cases and test patient-derived neuronal or organoid mitochondrial respiration and ATP production at measured concentrations, with isogenic ACY1 correction as a rescue control.

Show evidence (2 references)

PMID:37871522 SUPPORT In Vitro

"the in vitro effects of N-acetylglutamate (NAG) and N-acetylmethionine (NAM), major metabolites accumulating in ACY1 deficiency"

Establishes that the mechanistic evidence comes from in-vitro metabolite exposure.

PMID:17516490 REFUTE Human Clinical

"we found no evidence of an increased concentration of N-acetylated amino acids in the cerebrospinal fluid from one patient"

A single human CSF observation weighs against assuming CNS exposure, although it is not decisive.

Is congenital sensorineural hearing impairment a reproducible human ACY1 deficiency phenotype, and does the zebrafish auditory-hair-cell mechanism translate to the human inner ear?

HUMAN MODEL MISMATCH OPEN gap_acy1_hearing_replication

Attached to

pathophysiology#Auditory Hair-Cell Developmental Impairment phenotypes#Congenital sensorineural hearing impairment

The new report combines a single biochemically confirmed human case with a zebrafish morpholino phenotype and mRNA rescue. This is stronger than an isolated case association but remains vulnerable to single-family, morpholino, and cross-species limitations. The authors explicitly require additional unrelated patients and independent validation before ACY1 can be established as a hereditary hearing-loss gene.

Proposed experiments

Independent human hearing cohort replication and orthogonal model validation

exp_acy1_hearing_replication

Identify unrelated individuals with biallelic ACY1 deficiency and formal audiologic phenotyping, then reproduce the hair-cell phenotype in a stable acy1 knockout or human inner-ear organoid with wild-type rescue.

Show evidence (1 reference)

PMID:42322530 SUPPORT Human Clinical

"Our findings support ACY1 as a candidate gene for hereditary hearing impairment, although additional unrelated patients and independent validation are needed to further establish the gene-disease relationship."

The study authors directly state the candidate-level conclusion and replication requirement.

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Pathophysiology

5

Aminoacylase 1 Enzyme Deficiency

Biallelic pathogenic loss-of-function or missense variants in ACY1 abolish or reduce the activity of aminoacylase 1, a zinc-binding metalloenzyme that hydrolyzes N-acetyl amino acids into the free amino acid and acetate. Enzyme deficiency is demonstrable in patient-derived (EBV-transformed) lymphoblasts and reproduced by expression of mutant ACY1 in HEK293 cells, where most disease-associated mutations cause a nearly complete loss of enzyme function. This blocks the deacetylation/recycling step of amino-acid metabolism performed by the enzyme.

ACY1-dependent auditory hair-cell development

ACY1 hgnc:177

N-acetyl amino acid hydrolysis in amino acid metabolism GO:0042219 ↓ DECREASED

aminoacylase activity GO:0004046 ↓ DECREASED

Downstream

Accumulation and Urinary Excretion of N-Acetylated Amino Acids Failure to deacetylate N-acetyl amino acids leaves them to accumulate and be excreted in the urine.

Auditory Hair-Cell Developmental Impairment ACY1 knockdown reduced zebrafish auditory hair cells and function, with wild-type but not mutant human-mRNA rescue.

Show evidence (4 references)

PMID:16465618 SUPPORT Other

"Aminoacylase 1 (ACY1; EC 3.5.14) is the most abundant of the aminoacylases, a class of enzymes involved in hydrolysis of N-acetylated proteins."

Identifies aminoacylase 1 as the most abundant aminoacylase, the enzyme lost in this disorder.

PMID:21414403 SUPPORT Other

"Aminoacylase 1 is a zinc-binding enzyme which hydrolyzes N-acetyl amino acids"

Defines the enzyme as a zinc-binding hydrolase acting on N-acetyl amino acids, the reaction lost on deficiency.

PMID:21414403 SUPPORT In Vitro

"Most mutations resulted in a nearly complete loss of enzyme function"

HEK293 expression of disease-associated ACY1 variants shows most cause near-complete loss of enzyme activity.

+ 1 more reference

Accumulation and Urinary Excretion of N-Acetylated Amino Acids

Because the deacetylation step is blocked, N-acetylated amino acids accumulate and are excreted in the urine, producing the biochemical signature of the disease: a specific profile of ~11 N-acetylated amino acids on urine GC-MS/NMR (N-acetyl derivatives of methionine, glutamate, alanine, glycine, threonine, leucine, isoleucine, valine, serine, plus N-acetylglutamine and N-acetylasparagine). Notably, one study found no increase of N-acetylated amino acids in cerebrospinal fluid, leaving the consequences for brain metabolism unresolved.

N-acetylated amino-acid mitochondrial bioenergetic toxicity

deacetylation of N-acetylated amino acids GO:0042219 ↓ DECREASED

Downstream

Mitochondrial Brain Energy Impairment N-acetylglutamate and N-acetylmethionine directly impaired mitochondrial enzymes and ATP synthesis in vitro.

Heterogeneous Neurological Manifestations of Uncertain Causality Most ascertained patients have neurological findings, but whether the biochemical defect causes them is unresolved.

Show evidence (3 references)

PMID:16465618 SUPPORT Human Clinical

"increased urinary excretion of several N-acetylated amino acids"

The enzyme defect produces increased urinary excretion of N-acetylated amino acids, the biochemical hallmark.

PMID:17516490 SUPPORT Human Clinical

"A typical profile with 11 accumulating N-acetylated amino acids was observed in urine from the patients"

Defines the specific 11-metabolite urinary N-acetylated amino acid profile.

PMID:17516490 SUPPORT Human Clinical

"we found no evidence of an increased concentration of N-acetylated amino acids in the cerebrospinal fluid from one patient"

The absence of CSF accumulation leaves the consequences for brain metabolism unresolved.

Mitochondrial Brain Energy Impairment

In developing-rat brain mitochondrial preparations, N-acetylglutamate and N-acetylmethionine inhibited selected respiratory-chain and glutamate-dehydrogenase activities and strongly reduced ATP synthesis. This is a candidate toxic-metabolite mechanism, not a demonstrated human disease mechanism.

N-acetylated amino-acid mitochondrial bioenergetic toxicity

mitochondrial ATP synthesis coupled electron transport GO:0042775 ↓ DECREASED

Experimental models

Developing-rat brain mitochondrial metabolite-exposure preparation OTHER Tests whether two metabolites associated with ACY1 deficiency alter mitochondrial enzymes and ATP synthesis.

Downstream

Heterogeneous Neurological Manifestations of Uncertain Causality Mitochondrial energy impairment could contribute to neurological findings, but this has not been shown in affected humans.

Show evidence (1 reference)

PMID:37871522 SUPPORT In Vitro

"Finally, NAG and NAM strongly decreased mitochondrial ATP synthesis."

Directly supports reduced ATP synthesis in the in-vitro preparation.

Auditory Hair-Cell Developmental Impairment

Morpholino-mediated acy1 knockdown in zebrafish reduced auditory hair cells, impaired auditory function, and downregulated inner-ear developmental genes; wild-type but not mutant human ACY1 mRNA rescued the phenotype. The model is relevant to one human congenital-hearing-loss case but is not independently validated.

ACY1-dependent auditory hair-cell development

auditory hair cell CL:0000202

inner ear receptor cell development GO:0060119 ↓ DECREASED

Experimental models

Morpholino-mediated acy1-knockdown zebrafish auditory model OTHER Tests auditory hair-cell number, function, developmental-gene expression, and allele-specific rescue after acy1 knockdown.

Downstream

Congenital sensorineural hearing impairment Reduced auditory hair-cell number and function is a candidate mechanism for the single reported human hearing phenotype.

Show evidence (1 reference)

PMID:42322530 SUPPORT Model Organism

"transcriptomic profiling of zebrafish auditory hair cells, combining fluorescence-activated cell sorting (FACS) with RNA sequencing, revealed downregulation of critical inner ear development genes, including gfi1ab and atoh1a/b"

Supports impaired inner-ear developmental programs in the zebrafish model.

Heterogeneous Neurological Manifestations of Uncertain Causality

Most individuals ascertained with ACY1 deficiency have presented with heterogeneous, nonspecific neurological symptoms, and the disorder is thought to be underdiagnosed. However, because ACY1 has been evolutionarily conserved and is expressed in the CNS, a role in CNS function or development is conceivable but has not been demonstrated, and ascertainment through urine metabolic screening means it remains unresolved whether ACY1 deficiency is a true metabolic disease with pleiotropic clinical expression or a biochemical variant. This node is intentionally curated as a mechanism of uncertain causality (see the attached knowledge gap).

Downstream

Global developmental delay Psychomotor/developmental delay is among the reported findings.

Generalized hypotonia Marked muscular hypotonia was a presenting feature in one of the original subjects.

Febrile seizures Febrile seizures are among the reported neurological findings.

Moderate intellectual disability Moderate intellectual disability has been reported in affected individuals.

Autistic behavior An ACY1-deficient patient presented with autistic features.

Cerebellar vermis atrophy Atrophy of the cerebellar vermis was noted in one original subject.

Syringomyelia Syringomyelia was noted in one original subject.

Generalized dystonia A 63-year-old woman with generalized dystonia expanded the reported phenotype.

Mild intellectual disability Mild intellectual disability was reported in the proband of a three-sibling series.

Delayed speech and language development Severe speech delay was documented in a child with an exon-skipping ACY1 variant.

Show evidence (2 references)

PMID:20480396 SUPPORT Human Clinical

"Most of the patients reported so far have presented with rather heterogeneous neurologic symptoms"

Establishes the heterogeneous neurological presentation of the reported patient population.

PMID:16465618 SUPPORT Human Clinical

"a role in CNS function or development is conceivable but has yet to be demonstrated"

States that a causal CNS role is plausible but unproven, motivating the uncertain-causality framing.

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Pathograph

Use the checkboxes to hide or show graph categories. Hover nodes for evidence and cross-linked metadata.

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Phenotypes

11

Musculoskeletal 1

Generalized hypotonia HP:0001290

Show evidence (1 reference)

PMID:16465618 SUPPORT Human Clinical

"marked muscular hypotonia (one subject)"

Marked muscular hypotonia was a presenting feature in one original subject.

Nervous System 5

Global developmental delay HP:0001263

Show evidence (1 reference)

PMID:21414403 SUPPORT Human Clinical

"delay of psychomotor development and moderate mental retardation have been reported"

Reports psychomotor developmental delay among affected individuals.

Febrile seizures Febrile seizure (within the age range of 3 months to 6 years) HP:0002373

Show evidence (1 reference)

PMID:21414403 SUPPORT Human Clinical

"neurological findings such as febrile seizures"

Lists febrile seizures among the reported neurological findings.

Mild intellectual disability HP:0001256

Show evidence (1 reference)

PMID:38234346 SUPPORT Human Clinical

"We present a 14-year-old boy with mild intellectual disability, speech sound disorder and non-alcoholic fatty liver disease"

Directly documents mild intellectual disability in the proband.

Delayed speech and language development HP:0000750

Show evidence (1 reference)

PMID:24117009 SUPPORT Human Clinical

"a 6-year-old girl presenting severe intellectual disability, motor retardation, absence of spontaneous locomotor activity and severe speech delay"

Directly documents severe speech delay in an affected child.

Autistic behavior HP:0000729

Show evidence (1 reference)

PMID:20480396 SUPPORT Human Clinical

"This article reports the findings of an ACY1-deficient patient presenting with autistic features"

Documents autistic features in an ACY1-deficient patient.

Other 5

Moderate intellectual disability HP:0002342

Show evidence (1 reference)

PMID:21414403 SUPPORT Human Clinical

"delay of psychomotor development and moderate mental retardation have been reported"

Reports moderate intellectual disability among affected individuals.

Cerebellar vermis atrophy HP:0006855

Show evidence (1 reference)

PMID:16465618 SUPPORT Human Clinical

"atrophy of the vermis and syringomyelia (one subject)"

Cerebellar vermis atrophy was described in one original subject.

Syringomyelia HP:0003396

Show evidence (1 reference)

PMID:16465618 SUPPORT Human Clinical

"atrophy of the vermis and syringomyelia (one subject)"

Syringomyelia was described in one original subject.

Generalized dystonia HP:0007325

Onset: CHILDHOOD

Show evidence (1 reference)

PMID:26686503 SUPPORT Human Clinical

"developed dystonic symptoms that gradually evolved into generalized dystonia"

Documents generalized dystonia in an ACY1-deficient individual, expanding the phenotype.

Congenital sensorineural hearing impairment HP:0008527

Show evidence (2 references)

PMID:42322530 SUPPORT Human Clinical

"a homozygous splicing variant, c.1063-1G>A, in ACY1 as a plausible candidate variant in a 5-year-old girl with congenital hearing loss and normal developmental milestones over a 4-year follow-up"

Directly documents the single human case while preserving the authors' candidate-level interpretation.

PMID:42322530 SUPPORT Model Organism

"A zebrafish model with morpholino-mediated acy1 knockdown revealed a significant reduction in hair cells and impaired auditory function, which were effectively rescued by wild-type but not mutant human ACY1 mRNA."

Provides in-vivo functional support, but not independent human replication.

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Genetic Associations

1

ACY1 pathogenic variants

Gene: ACY1 hgnc:177

Autosomal recessive

Show evidence (5 references)

PMID:16274666 SUPPORT Human Clinical

"a homozygous c.1057 C>T transition, predicting a p.Arg353Cys substitution"

Identifies homozygous ACY1 c.1057C>T (p.Arg353Cys) in the first reported patient.

PMID:16274666 SUPPORT Human Clinical

"The mutation was also detected in 5/161 controls."

Directly supports the carrier-control observation and cautions against interpreting genotype without functional and biochemical evidence.

PMID:16274666 SUPPORT In Vitro

"the mutant protein had lost catalytic activity"

Protein-expression studies confirm loss of catalytic activity of the mutant enzyme, establishing pathogenicity.

+ 2 more references

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Medical Actions

1

Speech and language therapy

Action: speech language therapy Ontology label: Speech Language Therapy NCIT:C159273

A proband with mild intellectual disability and speech sound disorder received speech education with a reported good outcome. This is single-case symptomatic evidence and does not establish an ACY1-specific or disease-modifying treatment.

Show evidence (1 reference)

PMID:38234346 SUPPORT Human Clinical

"The proband underwent speech education with good outcome."

Directly supports benefit in one patient; it does not establish efficacy for ACY1 deficiency.

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Biochemical Markers

1

Urinary N-acetylated amino acids (Increased)

Show evidence (3 references)

PMID:16274666 SUPPORT Human Clinical

"High amounts of N-acetylated amino acids were detected by gas chromatography-mass spectrometry in the urine"

Establishes elevated urinary N-acetylated amino acids as the biochemical diagnostic marker.

PMID:17516490 SUPPORT Human Clinical

"providing a specific urinary profile of accumulating N-acetylated amino acids"

Defines the specific urinary N-acetylated amino acid profile at the metabolite level.

PMID:17516490 SUPPORT Human Clinical

"The concentrations of the accumulating metabolites are <20 micromol/L in serum from the patients. Interestingly we found no evidence of an increased concentration of N-acetylated amino acids in the cerebrospinal fluid from one patient."

Supports the serum and single-patient CSF limitations stated in the notes.

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Diagnosis

3

Urinary N-acetylated amino-acid profile by GC-MS or NMR

Detect the characteristic urinary profile of multiple N-acetylated amino acids by urine organic-acid GC-MS; NMR can confirm and further resolve the metabolite profile. The biochemical result establishes ACY1 enzyme deficiency only when interpreted with molecular or enzyme confirmation.

urine chemistry measurement NCIT:C61044

Results: Increased urinary N-acetylalanine, N-acetylmethionine, N-acetylglutamine, and other characteristic N-acetylated amino acids.

Show evidence (2 references)

PMID:38234346 SUPPORT Human Clinical

"It is diagnosed by detecting acetylated amino acids among the patient's urine organic acids by gas chromatography-mass spectrometry."

Directly identifies urinary organic-acid GC-MS as the diagnostic biochemical test.

PMID:17516490 SUPPORT Human Clinical

"Our data define aminoacylase 1 deficiency at the metabolite level providing a specific urinary profile of accumulating N-acetylated amino acids."

Supports the specificity of the NMR-defined urinary profile.

Biallelic ACY1 molecular confirmation

Confirm homozygous or compound-heterozygous pathogenic ACY1 variants and assess segregation. Splice-region variants may require RNA or in-vitro splicing studies to demonstrate aberrant transcripts.

genetic testing NCIT:C15709

Results: Biallelic pathogenic or likely pathogenic ACY1 variants consistent with recessive inheritance.

Show evidence (2 references)

PMID:16465618 SUPPORT Human Clinical

"Mutation analysis uncovered recessive loss-of-function or missense ACY1 mutations in all four individuals affected."

Directly supports biallelic ACY1 testing as etiologic confirmation.

PMID:42322530 SUPPORT In Vitro

"In vitro splicing assays showed that the c.1063-1G>A variant activated a cryptic splice site, causing aberrant splicing, a frameshift, and a premature stop codon."

Shows how functional splicing analysis can resolve a candidate splice variant.

Aminoacylase 1 enzyme-activity testing

Demonstration of deficient ACY1 activity in patient-derived lymphoblasts or fibroblasts provides functional confirmation, especially for novel or uncertain variants.

laboratory procedure NCIT:C25294

Results: Absent or markedly reduced aminoacylase 1 activity in patient-derived cells.

Show evidence (1 reference)

PMID:24117009 SUPPORT In Vitro

"Biochemical analysis showed absence of ACY1 enzyme activity in the patient's fibroblasts."

Directly demonstrates confirmatory enzyme testing in patient fibroblasts.

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Progression

1

Variable, often non-progressive neurodevelopmental course in reported siblings

Age: Childhood through adolescence

Three homozygous siblings had slightly different intellectual abilities; serial follow-up found no deterioration in mental skills. This small family cannot establish the natural history of ACY1 deficiency generally.

Show evidence (1 reference)

PMID:38234346 SUPPORT Human Clinical

"Follow-up examinations of the siblings revealed no deterioration in their mental skills."

Directly supports stability during follow-up in these three siblings only.

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Prevalence

1

Published literature through 2024

Cases In Literature Ultra Rare

A 2024 case report stated that only 15 cases had been reported; this is a literature count, not a population prevalence estimate.

Show evidence (1 reference)

PMID:38234346 SUPPORT Human Clinical

"Up to date, only 15 cases have been reported in the literature."

Directly supports the literature case count as of the report.

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Differential Diagnoses

1

Conditions with similar clinical presentations that must be differentiated from Aminoacylase 1 Deficiency:

Canavan disease MONDO:0010079

Overlapping Features Both disorders involve urinary N-acetylated metabolites, but Canavan disease is ASPA deficiency with prominent N-acetylaspartate accumulation and a characteristic leukodystrophy, whereas ACY1 deficiency produces a broader profile of aliphatic N-acetylated amino acids and is confirmed by ACY1 testing or enzyme assay.

Distinguishing Features

Markedly elevated urine N-acetylaspartate and biallelic ASPA variants favor Canavan disease.
A multi-metabolite urinary N-acetylated amino-acid profile with biallelic ACY1 variants or deficient ACY1 activity favors aminoacylase 1 deficiency.

Show evidence (1 reference)

PMID:39628365 SUPPORT Human Clinical

"Canavan disease (CD) is an ultra-rare autosomal recessive leukodystrophy caused by loss-of-function mutations in ASPA, which encodes aspartoacylase (ASPA), leading to accumulation of N-acetylaspartate (NAA)."

Directly supplies the gene, enzyme, metabolite, and leukodystrophy discriminator for Canavan disease.

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Experimental Models

2

Developing-rat brain mitochondrial metabolite-exposure preparation OTHER

Organism

Norway rat NCBITaxon:10116

Tissue

brain UBERON:0000955

Cell source

Isolated brain mitochondrial preparations from developing rats

Culture

In-vitro biochemical exposure and enzyme-activity assays

Publication

PMID:37871522

Pathograph links

Mitochondrial Brain Energy Impairment Tests whether two metabolites associated with ACY1 deficiency alter mitochondrial enzymes and ATP synthesis.

Show evidence (1 reference)

PMID:37871522 SUPPORT In Vitro

"Finally, NAG and NAM strongly decreased mitochondrial ATP synthesis."

Directly links the preparation to the modeled bioenergetic effect.

Findings

N-acetylglutamate and N-acetylmethionine reduced mitochondrial ATP synthesis and inhibited selected respiratory-chain and glutamate-dehydrogenase activities.

"Taken together, the data indicate that NAG and NAM impair mitochondrial brain energy homeostasis."

Show evidence (1 reference)

PMID:37871522 SUPPORT In Vitro

"Taken together, the data indicate that NAG and NAM impair mitochondrial brain energy homeostasis."

Direct summary of the experimental finding.

Show evidence (1 reference)

PMID:37871522 SUPPORT In Vitro

"the in vitro effects of N-acetylglutamate (NAG) and N-acetylmethionine (NAM), major metabolites accumulating in ACY1 deficiency"

Defines the model as an in-vitro metabolite-exposure experiment.

Morpholino-mediated acy1-knockdown zebrafish auditory model OTHER

Organism

zebrafish NCBITaxon:7955

Publication

PMID:42322530

Pathograph links

Auditory Hair-Cell Developmental Impairment Tests auditory hair-cell number, function, developmental-gene expression, and allele-specific rescue after acy1 knockdown.

Show evidence (1 reference)

PMID:42322530 SUPPORT Model Organism

"A zebrafish model with morpholino-mediated acy1 knockdown revealed a significant reduction in hair cells and impaired auditory function, which were effectively rescued by wild-type but not mutant human ACY1 mRNA."

Directly defines the perturbation, phenotype, and rescue result.

Findings

acy1 knockdown reduced auditory hair cells and function; wild-type but not mutant human ACY1 mRNA rescued the phenotype.

"A zebrafish model with morpholino-mediated acy1 knockdown revealed a significant reduction in hair cells and impaired auditory function, which were effectively rescued by wild-type but not mutant human ACY1 mRNA."

Show evidence (1 reference)

PMID:42322530 SUPPORT Model Organism

"A zebrafish model with morpholino-mediated acy1 knockdown revealed a significant reduction in hair cells and impaired auditory function, which were effectively rescued by wild-type but not mutant human ACY1 mRNA."

Directly supports the finding statement.

Show evidence (1 reference)

PMID:42322530 SUPPORT Model Organism

"A zebrafish model with morpholino-mediated acy1 knockdown revealed a significant reduction in hair cells and impaired auditory function"

Identifies the reported in-vivo experimental model and its principal phenotype.

{ }

Source YAML

click to show

name: Aminoacylase 1 Deficiency
category: Mendelian
creation_date: "2026-07-07T00:00:00Z"
synonyms:
- ACY1 deficiency
- ACY1D
- Aminoacylase I deficiency
- N-acyl-L-amino acid amidohydrolase deficiency
- Deficiency of the aminoacylase-1 enzyme
description: >
  Aminoacylase 1 deficiency (ACY1D) is a rare autosomal recessive inborn error
  of metabolism caused by biallelic pathogenic variants in ACY1, the gene
  encoding aminoacylase 1 — an abundant cytosolic zinc-binding metalloenzyme
  (EC 3.5.1.14) that hydrolyzes N-acetylated amino acids into the free amino
  acid and acetate. Loss of enzyme activity does not produce the toxic-metabolite
  intoxication seen in classic organic acidurias; instead it causes a
  characteristic accumulation and urinary excretion of N-acetylated amino acids
  (a specific profile of 11 metabolites, including the N-acetyl
  derivatives of methionine, glutamate, alanine, glycine, threonine, leucine,
  isoleucine, valine, and serine) that is detected on urine organic-acid GC-MS or NMR. It
  was first reported in 2005 and defined genetically in 2006. Only 15 cases
  had been reported by a 2024 sibling series. Most ascertained
  individuals have presented with heterogeneous, nonspecific neurological
  findings (psychomotor/developmental delay, muscular hypotonia, febrile
  seizures, intellectual disability, autistic behavior, and — in individual
  cases — cerebellar vermis atrophy, syringomyelia, or generalized dystonia),
  but because most cases were ascertained through targeted urine metabolic
  screening, the clinical significance and penetrance of the biochemical defect
  remain debated and it is considered underdiagnosed. dismech curates the enzyme
  defect and its biochemical signature as established, while explicitly framing
  the causal link to a uniform clinical phenotype as an open knowledge gap.
notes: >-
  No disease-specific treatment supported by the cited literature was identified
  during this review. Management claims beyond the directly reported speech
  education outcome are therefore left uncatalogued rather than inferred.
disease_term:
  preferred_term: aminoacylase 1 deficiency
  term:
    id: MONDO:0012368
    label: aminoacylase 1 deficiency
classifications:
  icimd_category:
  - classification_value: amino_acids_other
    notes: >-
      ICIMD (Ferreira et al. 2021, PMID:33340416): group "Other disorders of
      amino acid metabolism" under category "Disorders of amino acid
      metabolism". ACY1 deficiency disrupts deacetylation/recycling of
      N-acetylated amino acids and is assigned to the WP-005 other amino-acid
      metabolism package.
parents:
- Inborn Error of Metabolism
references:
- reference: PMID:16274666
  title: "Aminoacylase I deficiency: a novel inborn error of metabolism."
- reference: PMID:16465618
  title: "Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism."
- reference: PMID:17516490
  title: "NMR spectroscopy of aminoacylase 1 deficiency, a novel inborn error of metabolism."
- reference: PMID:20480396
  title: "Aminoacylase 1 deficiency associated with autistic behavior."
- reference: PMID:21414403
  title: "The molecular basis of aminoacylase 1 deficiency."
- reference: PMID:24117009
  title: "Aminoacylase I deficiency due to ACY1 mRNA exon skipping."
- reference: PMID:26686503
  title: "Expanding the phenotype in aminoacylase 1 (ACY1) deficiency: characterization of the molecular defect in a 63-year-old woman with generalized dystonia."
- reference: PMID:37871522
  title: "N-Acetylglutamate and N-acetylmethionine compromise mitochondrial bioenergetics homeostasis and glutamate oxidation in brain of developing rats: Potential implications for the pathogenesis of ACY1 deficiency."
- reference: PMID:38234346
  title: "Aminoacylase 1 deficiency: case report on three affected siblings."
- reference: PMID:39628365
  title: Urine N-Acetylaspartate Distinguishes Phenotypes in Canavan Disease.
- reference: PMID:42322530
  title: "A Splice-Site Variant in ACY1 Associated with Congenital Hearing Loss: Clinical, Biochemical, and Zebrafish Functional Evidence."
mechanistic_hypotheses:
- hypothesis_group_id: n_acetyl_mitochondrial_bioenergetic_hypothesis
  hypothesis_label: N-acetylated amino-acid mitochondrial bioenergetic toxicity
  status: EMERGING
  description: >-
    Accumulating N-acetylglutamate and N-acetylmethionine may impair neuronal
    mitochondrial respiratory-chain and glutamate-dehydrogenase activities and
    reduce ATP synthesis, providing a candidate link from the biochemical defect
    to neurological findings. The evidence is limited to in-vitro exposure of
    developing-rat brain mitochondrial preparations; human CSF accumulation was
    not detected in the one patient tested.
  evidence:
  - reference: PMID:37871522
    reference_title: "N-Acetylglutamate and N-acetylmethionine compromise mitochondrial bioenergetics homeostasis and glutamate oxidation in brain of developing rats: Potential implications for the pathogenesis of ACY1 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Finally, NAG and NAM strongly decreased mitochondrial ATP synthesis."
    explanation: Directly supports mitochondrial ATP impairment in the experimental preparation, but not in human brain.
- hypothesis_group_id: acy1_auditory_hair_cell_hypothesis
  hypothesis_label: ACY1-dependent auditory hair-cell development
  status: EMERGING
  description: >-
    ACY1 loss may impair auditory hair-cell development and function. This model
    is supported by a single human candidate case and by morpholino knockdown and
    rescue in zebrafish, but the gene-hearing-loss relationship requires
    unrelated human cases and independent replication.
  evidence:
  - reference: PMID:42322530
    reference_title: "A Splice-Site Variant in ACY1 Associated with Congenital Hearing Loss: Clinical, Biochemical, and Zebrafish Functional Evidence."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      A zebrafish model with morpholino-mediated acy1 knockdown revealed a
      significant reduction in hair cells and impaired auditory function,
      which were effectively rescued by wild-type but not mutant human ACY1 mRNA.
    explanation: In-vivo knockdown and allele-specific rescue support the candidate auditory mechanism, with morpholino and cross-species limitations.
  - reference: PMID:42322530
    reference_title: "A Splice-Site Variant in ACY1 Associated with Congenital Hearing Loss: Clinical, Biochemical, and Zebrafish Functional Evidence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a homozygous splicing variant, c.1063-1G>A, in ACY1 as a plausible candidate
      variant in a 5-year-old girl with congenital hearing loss and normal
      developmental milestones over a 4-year follow-up
    explanation: Supplies the single human observation while retaining the authors' candidate-level wording.
pathophysiology:
- name: Aminoacylase 1 Enzyme Deficiency
  biological_scale: MOLECULAR
  description: >
    Biallelic pathogenic loss-of-function or missense variants in ACY1 abolish
    or reduce the activity of aminoacylase 1, a zinc-binding metalloenzyme
    that hydrolyzes N-acetyl amino acids into the free amino acid and acetate.
    Enzyme deficiency is demonstrable in patient-derived (EBV-transformed)
    lymphoblasts and reproduced by expression of mutant ACY1 in HEK293 cells,
    where most disease-associated mutations cause a nearly complete loss of
    enzyme function. This blocks the deacetylation/recycling step of amino-acid
    metabolism performed by the enzyme.
  genes:
  - preferred_term: ACY1
    term:
      id: hgnc:177
      label: ACY1
  biological_processes:
  - preferred_term: N-acetyl amino acid hydrolysis in amino acid metabolism
    term:
      id: GO:0042219
      label: modified amino acid catabolic process
    modifier: DECREASED
  molecular_functions:
  - preferred_term: aminoacylase activity
    term:
      id: GO:0004046
      label: aminoacylase activity
    modifier: DECREASED
  evidence:
  - reference: PMID:16465618
    reference_title: "Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: >-
      Aminoacylase 1 (ACY1; EC 3.5.14) is the most abundant of the
      aminoacylases, a class of enzymes involved in hydrolysis of N-acetylated proteins.
    explanation: Identifies aminoacylase 1 as the most abundant aminoacylase, the enzyme lost in this disorder.
  - reference: PMID:21414403
    reference_title: "The molecular basis of aminoacylase 1 deficiency."
    supports: SUPPORT
    evidence_source: OTHER
    snippet: "Aminoacylase 1 is a zinc-binding enzyme which hydrolyzes N-acetyl amino acids"
    explanation: Defines the enzyme as a zinc-binding hydrolase acting on N-acetyl amino acids, the reaction lost on deficiency.
  - reference: PMID:21414403
    reference_title: "The molecular basis of aminoacylase 1 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Most mutations resulted in a nearly complete loss of enzyme function"
    explanation: HEK293 expression of disease-associated ACY1 variants shows most cause near-complete loss of enzyme activity.
  - reference: PMID:24117009
    reference_title: "Aminoacylase I deficiency due to ACY1 mRNA exon skipping."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      identified the new homozygous c.1001_1001+5del6 mutation, which alters the
      mRNA transcription leading to exon 13 skipping and inclusion of a premature
      stop codon (p.Lys308Glufs*7)
    explanation: A patient splice-region variant caused exon skipping and a premature stop codon.
  downstream:
  - target: Accumulation and Urinary Excretion of N-Acetylated Amino Acids
    causal_link_type: DIRECT
    description: >
      Failure to deacetylate N-acetyl amino acids leaves them to accumulate and
      be excreted in the urine.
    evidence:
    - reference: PMID:16465618
      reference_title: "Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        We conclude that ACY1 mutations in these children led to functional ACY1
        deficiency and excretion of N-acetylated amino acids.
      explanation: The founding genetic series directly links ACY1 variants, enzyme deficiency, and urinary metabolites.
  - target: Auditory Hair-Cell Developmental Impairment
    causal_link_type: DIRECT
    hypothesis_groups:
    - acy1_auditory_hair_cell_hypothesis
    description: ACY1 knockdown reduced zebrafish auditory hair cells and function, with wild-type but not mutant human-mRNA rescue.
    evidence:
    - reference: PMID:42322530
      reference_title: "A Splice-Site Variant in ACY1 Associated with Congenital Hearing Loss: Clinical, Biochemical, and Zebrafish Functional Evidence."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        A zebrafish model with morpholino-mediated acy1 knockdown revealed a
        significant reduction in hair cells and impaired auditory function,
        which were effectively rescued by wild-type but not mutant human ACY1 mRNA.
      explanation: Supports the modeled edge in zebrafish; human causality remains candidate-level.
- name: Accumulation and Urinary Excretion of N-Acetylated Amino Acids
  biological_scale: MOLECULAR
  description: >
    Because the deacetylation step is blocked, N-acetylated amino acids
    accumulate and are excreted in the urine, producing the biochemical
    signature of the disease: a specific profile of ~11 N-acetylated amino acids
    on urine GC-MS/NMR (N-acetyl derivatives of methionine, glutamate, alanine,
    glycine, threonine, leucine, isoleucine, valine, serine, plus
    N-acetylglutamine and N-acetylasparagine). Notably, one study found no increase of N-acetylated
    amino acids in cerebrospinal fluid, leaving the consequences for brain
    metabolism unresolved.
  biological_processes:
  - preferred_term: deacetylation of N-acetylated amino acids
    term:
      id: GO:0042219
      label: modified amino acid catabolic process
    modifier: DECREASED
  evidence:
  - reference: PMID:16465618
    reference_title: "Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "increased urinary excretion of several N-acetylated amino acids"
    explanation: The enzyme defect produces increased urinary excretion of N-acetylated amino acids, the biochemical hallmark.
  - reference: PMID:17516490
    reference_title: "NMR spectroscopy of aminoacylase 1 deficiency, a novel inborn error of metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "A typical profile with 11 accumulating N-acetylated amino acids was observed in urine from the patients"
    explanation: Defines the specific 11-metabolite urinary N-acetylated amino acid profile.
  - reference: PMID:17516490
    reference_title: "NMR spectroscopy of aminoacylase 1 deficiency, a novel inborn error of metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "we found no evidence of an increased concentration of N-acetylated amino acids in the cerebrospinal fluid from one patient"
    explanation: The absence of CSF accumulation leaves the consequences for brain metabolism unresolved.
  downstream:
  - target: Mitochondrial Brain Energy Impairment
    causal_link_type: DIRECT
    hypothesis_groups:
    - n_acetyl_mitochondrial_bioenergetic_hypothesis
    description: N-acetylglutamate and N-acetylmethionine directly impaired mitochondrial enzymes and ATP synthesis in vitro.
    evidence:
    - reference: PMID:37871522
      reference_title: "N-Acetylglutamate and N-acetylmethionine compromise mitochondrial bioenergetics homeostasis and glutamate oxidation in brain of developing rats: Potential implications for the pathogenesis of ACY1 deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Taken together, the data indicate that NAG and NAM impair mitochondrial brain energy homeostasis."
      explanation: Direct evidence in developing-rat brain mitochondrial preparations; it does not establish exposure or effect in human CNS.
  - target: Heterogeneous Neurological Manifestations of Uncertain Causality
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: >
      Most ascertained patients have neurological findings, but whether the
      biochemical defect causes them is unresolved.
    evidence:
    - reference: PMID:20480396
      reference_title: "Aminoacylase 1 deficiency associated with autistic behavior."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        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
      explanation: Directly supports the uncertainty and prevents the edge from being presented as established.
- name: Mitochondrial Brain Energy Impairment
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    In developing-rat brain mitochondrial preparations, N-acetylglutamate and
    N-acetylmethionine inhibited selected respiratory-chain and
    glutamate-dehydrogenase activities and strongly reduced ATP synthesis. This is a
    candidate toxic-metabolite mechanism, not a demonstrated human disease
    mechanism.
  biological_processes:
  - preferred_term: mitochondrial ATP synthesis coupled electron transport
    term:
      id: GO:0042775
      label: mitochondrial ATP synthesis coupled electron transport
    modifier: DECREASED
  evidence:
  - reference: PMID:37871522
    reference_title: "N-Acetylglutamate and N-acetylmethionine compromise mitochondrial bioenergetics homeostasis and glutamate oxidation in brain of developing rats: Potential implications for the pathogenesis of ACY1 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Finally, NAG and NAM strongly decreased mitochondrial ATP synthesis."
    explanation: Directly supports reduced ATP synthesis in the in-vitro preparation.
  downstream:
  - target: Heterogeneous Neurological Manifestations of Uncertain Causality
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - n_acetyl_mitochondrial_bioenergetic_hypothesis
    description: Mitochondrial energy impairment could contribute to neurological findings, but this has not been shown in affected humans.
    evidence:
    - reference: PMID:37871522
      reference_title: "N-Acetylglutamate and N-acetylmethionine compromise mitochondrial bioenergetics homeostasis and glutamate oxidation in brain of developing rats: Potential implications for the pathogenesis of ACY1 deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: >-
        Considering that the pathogenesis of ACY1 is practically unknown and the
        brain is highly dependent on energy production, the in vitro effects of
        N-acetylglutamate (NAG) and N-acetylmethionine (NAM), major metabolites
        accumulating in ACY1 deficiency
      explanation: The study explicitly frames the experiment as a pathogenesis hypothesis rather than human causal proof.
- name: Auditory Hair-Cell Developmental Impairment
  biological_scale: CELLULAR
  mechanism_confidence: HYPOTHETICAL
  description: >-
    Morpholino-mediated acy1 knockdown in zebrafish reduced auditory hair cells,
    impaired auditory function, and downregulated inner-ear developmental genes;
    wild-type but not mutant human ACY1 mRNA rescued the phenotype. The model is
    relevant to one human congenital-hearing-loss case but is not independently
    validated.
  cell_types:
  - preferred_term: auditory hair cell
    term:
      id: CL:0000202
      label: auditory hair cell
  biological_processes:
  - preferred_term: inner ear receptor cell development
    term:
      id: GO:0060119
      label: inner ear receptor cell development
    modifier: DECREASED
  evidence:
  - reference: PMID:42322530
    reference_title: "A Splice-Site Variant in ACY1 Associated with Congenital Hearing Loss: Clinical, Biochemical, and Zebrafish Functional Evidence."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      transcriptomic profiling of zebrafish auditory hair cells, combining
      fluorescence-activated cell sorting (FACS) with RNA sequencing, revealed
      downregulation of critical inner ear development genes, including gfi1ab
      and atoh1a/b
    explanation: Supports impaired inner-ear developmental programs in the zebrafish model.
  downstream:
  - target: Congenital sensorineural hearing impairment
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    hypothesis_groups:
    - acy1_auditory_hair_cell_hypothesis
    description: Reduced auditory hair-cell number and function is a candidate mechanism for the single reported human hearing phenotype.
    evidence:
    - reference: PMID:42322530
      reference_title: "A Splice-Site Variant in ACY1 Associated with Congenital Hearing Loss: Clinical, Biochemical, and Zebrafish Functional Evidence."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        A zebrafish model with morpholino-mediated acy1 knockdown revealed a
        significant reduction in hair cells and impaired auditory function
      explanation: Supports the phenotype edge in zebrafish, not definitive human gene-disease causality.
- name: Heterogeneous Neurological Manifestations of Uncertain Causality
  biological_scale: ORGANISM
  mechanism_confidence: HYPOTHETICAL
  description: >
    Most individuals ascertained with ACY1 deficiency have presented with
    heterogeneous, nonspecific neurological symptoms, and the disorder is
    thought to be underdiagnosed. However, because ACY1 has been evolutionarily
    conserved and is expressed in the CNS, a role in CNS function or development
    is conceivable but has not been demonstrated, and ascertainment through
    urine metabolic screening means it remains unresolved whether ACY1
    deficiency is a true metabolic disease with pleiotropic clinical expression
    or a biochemical variant. This node is intentionally curated as a mechanism
    of uncertain causality (see the attached knowledge gap).
  evidence:
  - reference: PMID:20480396
    reference_title: "Aminoacylase 1 deficiency associated with autistic behavior."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Most of the patients reported so far have presented with rather heterogeneous neurologic symptoms"
    explanation: Establishes the heterogeneous neurological presentation of the reported patient population.
  - reference: PMID:16465618
    reference_title: "Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a role in CNS function or development is conceivable but has yet to be demonstrated"
    explanation: States that a causal CNS role is plausible but unproven, motivating the uncertain-causality framing.
  downstream:
  - target: Global developmental delay
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Psychomotor/developmental delay is among the reported findings.
    evidence:
    - reference: PMID:21414403
      reference_title: "The molecular basis of aminoacylase 1 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "delay of psychomotor development and moderate mental retardation have been reported"
      explanation: Supports occurrence in affected individuals; it does not establish that ACY1 deficiency caused the finding.
  - target: Generalized hypotonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Marked muscular hypotonia was a presenting feature in one of the original subjects.
    evidence:
    - reference: PMID:16465618
      reference_title: "Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "marked muscular hypotonia (one subject)"
      explanation: Supports a single observed association, not causality.
  - target: Febrile seizures
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Febrile seizures are among the reported neurological findings.
    evidence:
    - reference: PMID:21414403
      reference_title: "The molecular basis of aminoacylase 1 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "neurological findings such as febrile seizures"
      explanation: Supports reported occurrence, not a causal mechanism.
  - target: Moderate intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Moderate intellectual disability has been reported in affected individuals.
    evidence:
    - reference: PMID:21414403
      reference_title: "The molecular basis of aminoacylase 1 deficiency."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "delay of psychomotor development and moderate mental retardation have been reported"
      explanation: Supports reported occurrence, not penetrance or causality.
  - target: Autistic behavior
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: An ACY1-deficient patient presented with autistic features.
    evidence:
    - reference: PMID:20480396
      reference_title: "Aminoacylase 1 deficiency associated with autistic behavior."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "This article reports the findings of an ACY1-deficient patient presenting with autistic features"
      explanation: Supports a single-patient association, not causality.
  - target: Cerebellar vermis atrophy
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Atrophy of the cerebellar vermis was noted in one original subject.
    evidence:
    - reference: PMID:16465618
      reference_title: "Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "atrophy of the vermis and syringomyelia (one subject)"
      explanation: Supports a single-patient association, not causality.
  - target: Syringomyelia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Syringomyelia was noted in one original subject.
    evidence:
    - reference: PMID:16465618
      reference_title: "Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "atrophy of the vermis and syringomyelia (one subject)"
      explanation: Supports a single-patient association, not causality.
  - target: Generalized dystonia
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: A 63-year-old woman with generalized dystonia expanded the reported phenotype.
    evidence:
    - reference: PMID:26686503
      reference_title: "Expanding the phenotype in aminoacylase 1 (ACY1) deficiency: characterization of the molecular defect in a 63-year-old woman with generalized dystonia."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "developed dystonic symptoms that gradually evolved into generalized dystonia"
      explanation: Supports a single-patient association, not causality.
  - target: Mild intellectual disability
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Mild intellectual disability was reported in the proband of a three-sibling series.
    evidence:
    - reference: PMID:38234346
      reference_title: "Aminoacylase 1 deficiency: case report on three affected siblings."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "We present a 14-year-old boy with mild intellectual disability, speech sound disorder and non-alcoholic fatty liver disease"
      explanation: Supports a single-patient association, not causality.
  - target: Delayed speech and language development
    causal_link_type: INDIRECT_UNKNOWN_INTERMEDIATES
    description: Severe speech delay was documented in a child with an exon-skipping ACY1 variant.
    evidence:
    - reference: PMID:24117009
      reference_title: "Aminoacylase I deficiency due to ACY1 mRNA exon skipping."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: >-
        a 6-year-old girl presenting severe intellectual disability, motor
        retardation, absence of spontaneous locomotor activity and severe speech delay
      explanation: Supports a single-patient association, not causality.
phenotypes:
- name: Global developmental delay
  description: >
    Psychomotor / developmental delay has been reported, and affected
    individuals have been ascertained during evaluation of nonspecific
    psychomotor delay.
  phenotype_term:
    preferred_term: Psychomotor developmental delay
    term:
      id: HP:0001263
      label: Global developmental delay
  evidence:
  - reference: PMID:21414403
    reference_title: "The molecular basis of aminoacylase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "delay of psychomotor development and moderate mental retardation have been reported"
    explanation: Reports psychomotor developmental delay among affected individuals.
- name: Generalized hypotonia
  description: >
    Marked muscular hypotonia was the presenting feature prompting metabolic
    screening in one of the four originally genetically defined subjects.
  phenotype_term:
    preferred_term: Marked muscular hypotonia
    term:
      id: HP:0001290
      label: Generalized hypotonia
  evidence:
  - reference: PMID:16465618
    reference_title: "Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "marked muscular hypotonia (one subject)"
    explanation: Marked muscular hypotonia was a presenting feature in one original subject.
- name: Febrile seizures
  description: >
    Febrile seizures are among the neurological findings reported in ACY1
    deficiency.
  phenotype_term:
    preferred_term: Febrile seizures
    term:
      id: HP:0002373
      label: Febrile seizure (within the age range of 3 months to 6 years)
  evidence:
  - reference: PMID:21414403
    reference_title: "The molecular basis of aminoacylase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "neurological findings such as febrile seizures"
    explanation: Lists febrile seizures among the reported neurological findings.
- name: Moderate intellectual disability
  description: >
    Moderate intellectual disability (historically "moderate mental
    retardation") has been reported in affected individuals.
  phenotype_term:
    preferred_term: Moderate intellectual disability
    term:
      id: HP:0002342
      label: Moderate intellectual disability
  evidence:
  - reference: PMID:21414403
    reference_title: "The molecular basis of aminoacylase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "delay of psychomotor development and moderate mental retardation have been reported"
    explanation: Reports moderate intellectual disability among affected individuals.
- name: Mild intellectual disability
  description: >-
    Mild intellectual disability was reported in the proband of a recent
    three-sibling series; his brothers had slightly varied intellectual
    abilities, and follow-up showed no deterioration.
  phenotype_term:
    preferred_term: Mild intellectual disability
    term:
      id: HP:0001256
      label: Mild intellectual disability
  evidence:
  - reference: PMID:38234346
    reference_title: "Aminoacylase 1 deficiency: case report on three affected siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "We present a 14-year-old boy with mild intellectual disability, speech sound disorder and non-alcoholic fatty liver disease"
    explanation: Directly documents mild intellectual disability in the proband.
- name: Delayed speech and language development
  description: >-
    Severe speech delay and absent speech are part of the reported neurological
    spectrum, including a child with an exon-skipping ACY1 variant.
  phenotype_term:
    preferred_term: Delayed speech and language development
    term:
      id: HP:0000750
      label: Delayed speech and language development
  evidence:
  - reference: PMID:24117009
    reference_title: "Aminoacylase I deficiency due to ACY1 mRNA exon skipping."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a 6-year-old girl presenting severe intellectual disability, motor
      retardation, absence of spontaneous locomotor activity and severe speech delay
    explanation: Directly documents severe speech delay in an affected child.
- name: Autistic behavior
  description: >
    An ACY1-deficient patient presented with autistic features.
  phenotype_term:
    preferred_term: Autistic features
    term:
      id: HP:0000729
      label: Autistic behavior
  evidence:
  - reference: PMID:20480396
    reference_title: "Aminoacylase 1 deficiency associated with autistic behavior."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "This article reports the findings of an ACY1-deficient patient presenting with autistic features"
    explanation: Documents autistic features in an ACY1-deficient patient.
- name: Cerebellar vermis atrophy
  description: >
    Atrophy of the cerebellar vermis was an imaging finding in one of the
    originally described subjects (presenting with psychomotor delay).
  phenotype_term:
    preferred_term: Atrophy of the vermis
    term:
      id: HP:0006855
      label: Cerebellar vermis atrophy
  evidence:
  - reference: PMID:16465618
    reference_title: "Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "atrophy of the vermis and syringomyelia (one subject)"
    explanation: Cerebellar vermis atrophy was described in one original subject.
- name: Syringomyelia
  description: >
    Syringomyelia was noted alongside cerebellar vermis atrophy in one of the
    originally described subjects.
  phenotype_term:
    preferred_term: Syringomyelia
    term:
      id: HP:0003396
      label: Syringomyelia
  evidence:
  - reference: PMID:16465618
    reference_title: "Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "atrophy of the vermis and syringomyelia (one subject)"
    explanation: Syringomyelia was described in one original subject.
- name: Generalized dystonia
  description: >
    A cognitively normal 63-year-old woman developed dystonic symptoms from
    around age 12 that evolved into generalized dystonia, expanding the reported
    clinical spectrum.
  phenotype_term:
    preferred_term: Generalized dystonia
    term:
      id: HP:0007325
      label: Generalized dystonia
    onset:
      onset_category: CHILDHOOD
  evidence:
  - reference: PMID:26686503
    reference_title: "Expanding the phenotype in aminoacylase 1 (ACY1) deficiency: characterization of the molecular defect in a 63-year-old woman with generalized dystonia."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "developed dystonic symptoms that gradually evolved into generalized dystonia"
    explanation: Documents generalized dystonia in an ACY1-deficient individual, expanding the phenotype.
- name: Congenital sensorineural hearing impairment
  description: >-
    Congenital hearing loss was reported in one child with confirmed ACY1
    deficiency and normal developmental milestones. ACY1 remains a candidate
    hearing-loss gene pending unrelated cases and independent validation.
  phenotype_term:
    preferred_term: Congenital sensorineural hearing impairment
    term:
      id: HP:0008527
      label: Congenital sensorineural hearing impairment
  evidence:
  - reference: PMID:42322530
    reference_title: "A Splice-Site Variant in ACY1 Associated with Congenital Hearing Loss: Clinical, Biochemical, and Zebrafish Functional Evidence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      a homozygous splicing variant, c.1063-1G>A, in ACY1 as a plausible candidate
      variant in a 5-year-old girl with congenital hearing loss and normal
      developmental milestones over a 4-year follow-up
    explanation: Directly documents the single human case while preserving the authors' candidate-level interpretation.
  - reference: PMID:42322530
    reference_title: "A Splice-Site Variant in ACY1 Associated with Congenital Hearing Loss: Clinical, Biochemical, and Zebrafish Functional Evidence."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      A zebrafish model with morpholino-mediated acy1 knockdown revealed a
      significant reduction in hair cells and impaired auditory function,
      which were effectively rescued by wild-type but not mutant human ACY1 mRNA.
    explanation: Provides in-vivo functional support, but not independent human replication.
biochemical:
- name: Urinary N-acetylated amino acids
  presence: Increased
  evidence:
  - reference: PMID:16274666
    reference_title: "Aminoacylase I deficiency: a novel inborn error of metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "High amounts of N-acetylated amino acids were detected by gas chromatography-mass spectrometry in the urine"
    explanation: Establishes elevated urinary N-acetylated amino acids as the biochemical diagnostic marker.
  - reference: PMID:17516490
    reference_title: "NMR spectroscopy of aminoacylase 1 deficiency, a novel inborn error of metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "providing a specific urinary profile of accumulating N-acetylated amino acids"
    explanation: Defines the specific urinary N-acetylated amino acid profile at the metabolite level.
  - reference: PMID:17516490
    reference_title: "NMR spectroscopy of aminoacylase 1 deficiency, a novel inborn error of metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      The concentrations of the accumulating metabolites are <20 micromol/L in
      serum from the patients. Interestingly we found no evidence of an increased
      concentration of N-acetylated amino acids in the cerebrospinal fluid from one patient.
    explanation: Supports the serum and single-patient CSF limitations stated in the notes.
  notes: >
    Detected by urine organic-acid GC-MS and confirmed by NMR; the profile
    includes the N-acetyl derivatives of methionine, glutamate, alanine,
    glycine, threonine, leucine, isoleucine, valine, and serine, plus
    N-acetylglutamine and N-acetylasparagine. Serum concentrations are low (<20 micromol/L) and, in
    one study, cerebrospinal-fluid levels were not elevated.
prevalence:
- population: Published literature through 2024
  measure_type: CASES_IN_LITERATURE
  prevalence_class: ULTRA_RARE
  notes: A 2024 case report stated that only 15 cases had been reported; this is a literature count, not a population prevalence estimate.
  evidence:
  - reference: PMID:38234346
    reference_title: "Aminoacylase 1 deficiency: case report on three affected siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Up to date, only 15 cases have been reported in the literature."
    explanation: Directly supports the literature case count as of the report.
progression:
- phase: Variable, often non-progressive neurodevelopmental course in reported siblings
  age_range: Childhood through adolescence
  notes: >-
    Three homozygous siblings had slightly different intellectual abilities;
    serial follow-up found no deterioration in mental skills. This small family
    cannot establish the natural history of ACY1 deficiency generally.
  evidence:
  - reference: PMID:38234346
    reference_title: "Aminoacylase 1 deficiency: case report on three affected siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Follow-up examinations of the siblings revealed no deterioration in their mental skills."
    explanation: Directly supports stability during follow-up in these three siblings only.
genetic:
- name: ACY1 pathogenic variants
  gene_term:
    preferred_term: ACY1
    term:
      id: hgnc:177
      label: ACY1
  inheritance:
  - name: Autosomal recessive
    evidence:
    - reference: PMID:16465618
      reference_title: "Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism."
      supports: SUPPORT
      evidence_source: HUMAN_CLINICAL
      snippet: "Mutation analysis uncovered recessive loss-of-function or missense ACY1 mutations in all four individuals affected"
      explanation: Recessive ACY1 mutations in all four affected individuals establish autosomal recessive inheritance.
  features: >
    Biallelic ACY1 variants cause aminoacylase 1 deficiency. A recurrent
    missense variant, c.1057C>T (p.Arg353Cys), is seen homozygously in multiple
    unrelated patients; it was also detected heterozygously in 5/161 controls,
    and protein-expression studies confirmed that the mutant protein had lost
    catalytic activity. Additional loss-of-function and missense variants have
    been reported, and expression of most disease-associated variants in HEK293
    cells shows a near-complete loss of enzyme activity.
  evidence:
  - reference: PMID:16274666
    reference_title: "Aminoacylase I deficiency: a novel inborn error of metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "a homozygous c.1057 C>T transition, predicting a p.Arg353Cys substitution"
    explanation: Identifies homozygous ACY1 c.1057C>T (p.Arg353Cys) in the first reported patient.
  - reference: PMID:16274666
    reference_title: "Aminoacylase I deficiency: a novel inborn error of metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation was also detected in 5/161 controls."
    explanation: Directly supports the carrier-control observation and cautions against interpreting genotype without functional and biochemical evidence.
  - reference: PMID:16274666
    reference_title: "Aminoacylase I deficiency: a novel inborn error of metabolism."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "the mutant protein had lost catalytic activity"
    explanation: Protein-expression studies confirm loss of catalytic activity of the mutant enzyme, establishing pathogenicity.
  - reference: PMID:20480396
    reference_title: "Aminoacylase 1 deficiency associated with autistic behavior."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The mutation analysis showed a homozygous c.1057C>T transition, predicting a p.Arg353Cys substitution."
    explanation: Documents recurrence of homozygous p.Arg353Cys in an unrelated reported patient.
  - reference: PMID:21414403
    reference_title: "The molecular basis of aminoacylase 1 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Most mutations resulted in a nearly complete loss of enzyme function."
    explanation: Supports the functional effect of most tested disease-associated variants.
inheritance:
- name: Autosomal recessive
  inheritance_term:
    preferred_term: Autosomal recessive inheritance
    term:
      id: HP:0000007
      label: Autosomal recessive inheritance
  evidence:
  - reference: PMID:21414403
    reference_title: "The molecular basis of aminoacylase 1 deficiency."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "follows an autosomal-recessive trait of inheritance"
    explanation: States that aminoacylase 1 deficiency is inherited in an autosomal recessive manner.
diagnosis:
- name: Urinary N-acetylated amino-acid profile by GC-MS or NMR
  description: >-
    Detect the characteristic urinary profile of multiple N-acetylated amino
    acids by urine organic-acid GC-MS; NMR can confirm and further resolve the
    metabolite profile. The biochemical result establishes ACY1 enzyme
    deficiency only when interpreted with molecular or enzyme confirmation.
  diagnosis_term:
    preferred_term: urine chemistry measurement
    term:
      id: NCIT:C61044
      label: Urine Chemistry Measurement
  results: Increased urinary N-acetylalanine, N-acetylmethionine, N-acetylglutamine, and other characteristic N-acetylated amino acids.
  evidence:
  - reference: PMID:38234346
    reference_title: "Aminoacylase 1 deficiency: case report on three affected siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "It is diagnosed by detecting acetylated amino acids among the patient's urine organic acids by gas chromatography-mass spectrometry."
    explanation: Directly identifies urinary organic-acid GC-MS as the diagnostic biochemical test.
  - reference: PMID:17516490
    reference_title: "NMR spectroscopy of aminoacylase 1 deficiency, a novel inborn error of metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Our data define aminoacylase 1 deficiency at the metabolite level providing a specific urinary profile of accumulating N-acetylated amino acids."
    explanation: Supports the specificity of the NMR-defined urinary profile.
- name: Biallelic ACY1 molecular confirmation
  description: >-
    Confirm homozygous or compound-heterozygous pathogenic ACY1 variants and
    assess segregation. Splice-region variants may require RNA or in-vitro
    splicing studies to demonstrate aberrant transcripts.
  diagnosis_term:
    preferred_term: genetic testing
    term:
      id: NCIT:C15709
      label: Genetic Testing
  results: Biallelic pathogenic or likely pathogenic ACY1 variants consistent with recessive inheritance.
  evidence:
  - reference: PMID:16465618
    reference_title: "Mutations in ACY1, the gene encoding aminoacylase 1, cause a novel inborn error of metabolism."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Mutation analysis uncovered recessive loss-of-function or missense ACY1 mutations in all four individuals affected."
    explanation: Directly supports biallelic ACY1 testing as etiologic confirmation.
  - reference: PMID:42322530
    reference_title: "A Splice-Site Variant in ACY1 Associated with Congenital Hearing Loss: Clinical, Biochemical, and Zebrafish Functional Evidence."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      In vitro splicing assays showed that the c.1063-1G>A variant activated a
      cryptic splice site, causing aberrant splicing, a frameshift, and a
      premature stop codon.
    explanation: Shows how functional splicing analysis can resolve a candidate splice variant.
- name: Aminoacylase 1 enzyme-activity testing
  description: >-
    Demonstration of deficient ACY1 activity in patient-derived lymphoblasts or
    fibroblasts provides functional confirmation, especially for novel or
    uncertain variants.
  diagnosis_term:
    preferred_term: laboratory procedure
    term:
      id: NCIT:C25294
      label: Laboratory Procedure
  results: Absent or markedly reduced aminoacylase 1 activity in patient-derived cells.
  evidence:
  - reference: PMID:24117009
    reference_title: "Aminoacylase I deficiency due to ACY1 mRNA exon skipping."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: "Biochemical analysis showed absence of ACY1 enzyme activity in the patient's fibroblasts."
    explanation: Directly demonstrates confirmatory enzyme testing in patient fibroblasts.
differential_diagnoses:
- name: Canavan disease
  disease_term:
    preferred_term: Canavan disease
    term:
      id: MONDO:0010079
      label: Canavan disease
  description: >-
    Both disorders involve urinary N-acetylated metabolites, but Canavan disease
    is ASPA deficiency with prominent N-acetylaspartate accumulation and a
    characteristic leukodystrophy, whereas ACY1 deficiency produces a broader
    profile of aliphatic N-acetylated amino acids and is confirmed by ACY1
    testing or enzyme assay.
  distinguishing_features:
  - Markedly elevated urine N-acetylaspartate and biallelic ASPA variants favor Canavan disease.
  - A multi-metabolite urinary N-acetylated amino-acid profile with biallelic ACY1 variants or deficient ACY1 activity favors aminoacylase 1 deficiency.
  evidence:
  - reference: PMID:39628365
    reference_title: Urine N-Acetylaspartate Distinguishes Phenotypes in Canavan Disease.
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Canavan disease (CD) is an ultra-rare autosomal recessive leukodystrophy
      caused by loss-of-function mutations in ASPA, which encodes
      aspartoacylase (ASPA), leading to accumulation of N-acetylaspartate (NAA).
    explanation: Directly supplies the gene, enzyme, metabolite, and leukodystrophy discriminator for Canavan disease.
treatments:
- name: Speech and language therapy
  description: >-
    A proband with mild intellectual disability and speech sound disorder
    received speech education with a reported good outcome. This is single-case
    symptomatic evidence and does not establish an ACY1-specific or
    disease-modifying treatment.
  therapeutic_modality: BEHAVIORAL
  treatment_term:
    preferred_term: speech language therapy
    term:
      id: NCIT:C159273
      label: Speech Language Therapy
  evidence:
  - reference: PMID:38234346
    reference_title: "Aminoacylase 1 deficiency: case report on three affected siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "The proband underwent speech education with good outcome."
    explanation: Directly supports benefit in one patient; it does not establish efficacy for ACY1 deficiency.
clinical_trials: []
experimental_models:
- name: Developing-rat brain mitochondrial metabolite-exposure preparation
  experimental_model_type: OTHER
  organism:
    preferred_term: Norway rat
    term:
      id: NCBITaxon:10116
      label: Rattus norvegicus
  tissue_term:
    preferred_term: brain
    term:
      id: UBERON:0000955
      label: brain
  cell_source: Isolated brain mitochondrial preparations from developing rats
  culture_system: In-vitro biochemical exposure and enzyme-activity assays
  conditions:
  - N-acetylglutamate exposure
  - N-acetylmethionine exposure
  - Unexposed control preparations
  publication: PMID:37871522
  modeled_mechanisms:
  - target: Mitochondrial Brain Energy Impairment
    description: Tests whether two metabolites associated with ACY1 deficiency alter mitochondrial enzymes and ATP synthesis.
    evidence:
    - reference: PMID:37871522
      reference_title: "N-Acetylglutamate and N-acetylmethionine compromise mitochondrial bioenergetics homeostasis and glutamate oxidation in brain of developing rats: Potential implications for the pathogenesis of ACY1 deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Finally, NAG and NAM strongly decreased mitochondrial ATP synthesis."
      explanation: Directly links the preparation to the modeled bioenergetic effect.
  findings:
  - statement: N-acetylglutamate and N-acetylmethionine reduced mitochondrial ATP synthesis and inhibited selected respiratory-chain and glutamate-dehydrogenase activities.
    supporting_text: "Taken together, the data indicate that NAG and NAM impair mitochondrial brain energy homeostasis."
    evidence:
    - reference: PMID:37871522
      reference_title: "N-Acetylglutamate and N-acetylmethionine compromise mitochondrial bioenergetics homeostasis and glutamate oxidation in brain of developing rats: Potential implications for the pathogenesis of ACY1 deficiency."
      supports: SUPPORT
      evidence_source: IN_VITRO
      snippet: "Taken together, the data indicate that NAG and NAM impair mitochondrial brain energy homeostasis."
      explanation: Direct summary of the experimental finding.
  evidence:
  - reference: PMID:37871522
    reference_title: "N-Acetylglutamate and N-acetylmethionine compromise mitochondrial bioenergetics homeostasis and glutamate oxidation in brain of developing rats: Potential implications for the pathogenesis of ACY1 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the in vitro effects of N-acetylglutamate (NAG) and N-acetylmethionine
      (NAM), major metabolites accumulating in ACY1 deficiency
    explanation: Defines the model as an in-vitro metabolite-exposure experiment.
- name: Morpholino-mediated acy1-knockdown zebrafish auditory model
  experimental_model_type: OTHER
  organism:
    preferred_term: zebrafish
    term:
      id: NCBITaxon:7955
      label: Danio rerio
  conditions:
  - Morpholino-mediated acy1 knockdown
  - Wild-type human ACY1 mRNA rescue
  - Mutant human ACY1 mRNA rescue
  publication: PMID:42322530
  modeled_mechanisms:
  - target: Auditory Hair-Cell Developmental Impairment
    description: Tests auditory hair-cell number, function, developmental-gene expression, and allele-specific rescue after acy1 knockdown.
    evidence:
    - reference: PMID:42322530
      reference_title: "A Splice-Site Variant in ACY1 Associated with Congenital Hearing Loss: Clinical, Biochemical, and Zebrafish Functional Evidence."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        A zebrafish model with morpholino-mediated acy1 knockdown revealed a
        significant reduction in hair cells and impaired auditory function,
        which were effectively rescued by wild-type but not mutant human ACY1 mRNA.
      explanation: Directly defines the perturbation, phenotype, and rescue result.
  findings:
  - statement: acy1 knockdown reduced auditory hair cells and function; wild-type but not mutant human ACY1 mRNA rescued the phenotype.
    supporting_text: >-
      A zebrafish model with morpholino-mediated acy1 knockdown revealed a
      significant reduction in hair cells and impaired auditory function,
      which were effectively rescued by wild-type but not mutant human ACY1 mRNA.
    evidence:
    - reference: PMID:42322530
      reference_title: "A Splice-Site Variant in ACY1 Associated with Congenital Hearing Loss: Clinical, Biochemical, and Zebrafish Functional Evidence."
      supports: SUPPORT
      evidence_source: MODEL_ORGANISM
      snippet: >-
        A zebrafish model with morpholino-mediated acy1 knockdown revealed a
        significant reduction in hair cells and impaired auditory function,
        which were effectively rescued by wild-type but not mutant human ACY1 mRNA.
      explanation: Directly supports the finding statement.
  evidence:
  - reference: PMID:42322530
    reference_title: "A Splice-Site Variant in ACY1 Associated with Congenital Hearing Loss: Clinical, Biochemical, and Zebrafish Functional Evidence."
    supports: SUPPORT
    evidence_source: MODEL_ORGANISM
    snippet: >-
      A zebrafish model with morpholino-mediated acy1 knockdown revealed a
      significant reduction in hair cells and impaired auditory function
    explanation: Identifies the reported in-vivo experimental model and its principal phenotype.
datasets: []
computational_models: []
discussions:
- discussion_id: gap_acy1_clinical_significance
  prompt: >-
    Is aminoacylase 1 deficiency a true metabolic disease that causally produces
    its reported neurological phenotypes (psychomotor delay, hypotonia, febrile
    seizures, intellectual disability, autism, dystonia), or is the enzyme
    defect largely a benign biochemical variant whose clinical associations
    reflect ascertainment bias from urine metabolic screening?
  kind: KNOWLEDGE_GAP
  status: OPEN
  attaches_to:
  - pathophysiology#Heterogeneous Neurological Manifestations of Uncertain Causality
  - pathophysiology#Accumulation and Urinary Excretion of N-Acetylated Amino Acids
  rationale: >-
    The enzymatic and biochemical basis of aminoacylase 1 deficiency is well
    established: biallelic ACY1 loss-of-function variants abolish hydrolysis of
    N-acetyl amino acids and produce a specific urinary N-acetylated amino acid
    profile. What remains unresolved is the causal link between this defect and
    clinical disease. Most affected individuals were ascertained through urine
    metabolic screening rather than a defining clinical phenotype, the reported
    neurological findings are heterogeneous and nonspecific, one original subject
    had normal clinical findings, one report found no increase of N-acetylated
    amino acids in cerebrospinal fluid, and at least one affected adult was
    cognitively normal. The authors of the defining studies explicitly could not
    state whether ACY1 deficiency has pathogenic significance with pleiotropic
    clinical expression or is simply a biochemical variant. Resolving this bears
    directly on genetic counseling, newborn/metabolic screening interpretation,
    and whether the condition should be treated as a disease.
  evidence:
  - reference: PMID:20480396
    reference_title: "Aminoacylase 1 deficiency associated with autistic behavior."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      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
    explanation: The clinical-significance uncertainty is stated directly by the case-report authors.
  - reference: PMID:38234346
    reference_title: "Aminoacylase 1 deficiency: case report on three affected siblings."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: "Its clinical manifestations are highly variable, ranging from severe neurological symptoms to being asymptomatic."
    explanation: Recent case literature confirms that clinical variability and asymptomatic disease remain central limitations.
  proposed_experiments:
  - experiment_id: exp_acy1_unbiased_cohort_penetrance
    name: Ascertainment-unbiased penetrance of ACY1 biallelic loss of function
    description: >-
      Estimate the neurodevelopmental phenotype rate among individuals with
      biallelic ACY1 loss-of-function genotypes identified in large,
      phenotype-agnostic sequencing biobanks (rather than metabolic-screening
      cohorts), comparing against matched controls to test whether the genotype
      is associated with neurological disease independent of ascertainment bias.
  - experiment_id: exp_acy1_cns_model
    name: CNS consequences of ACY1 loss in a neural model system
    description: >-
      Use ACY1-null human iPSC-derived neurons/organoids and/or an animal model
      to test whether loss of aminoacylase 1 perturbs neuronal metabolism,
      development, or function, given that ACY1 is expressed in the CNS but no
      accumulation of N-acetylated amino acids was detected in patient CSF.
- discussion_id: gap_acy1_mitochondrial_model_translation
  prompt: >-
    Do N-acetylglutamate and N-acetylmethionine reach concentrations in human
    brain that impair mitochondrial energy metabolism, as they do in exposed
    developing-rat brain mitochondrial preparations?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Mitochondrial Brain Energy Impairment
  - pathophysiology#Accumulation and Urinary Excretion of N-Acetylated Amino Acids
  rationale: >-
    Experimental evidence now identifies a plausible bioenergetic mechanism,
    but the preparation was outside an intact organism and did not establish
    metabolite exposure in human brain. The only reported patient CSF
    measurement found no increased N-acetylated amino acids, so translating the
    experimental effect to human neurological disease requires exposure and
    target-engagement evidence.
  evidence:
  - reference: PMID:37871522
    reference_title: "N-Acetylglutamate and N-acetylmethionine compromise mitochondrial bioenergetics homeostasis and glutamate oxidation in brain of developing rats: Potential implications for the pathogenesis of ACY1 deficiency."
    supports: SUPPORT
    evidence_source: IN_VITRO
    snippet: >-
      the in vitro effects of N-acetylglutamate (NAG) and N-acetylmethionine
      (NAM), major metabolites accumulating in ACY1 deficiency
    explanation: Establishes that the mechanistic evidence comes from in-vitro metabolite exposure.
  - reference: PMID:17516490
    reference_title: "NMR spectroscopy of aminoacylase 1 deficiency, a novel inborn error of metabolism."
    supports: REFUTE
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      we found no evidence of an increased concentration of N-acetylated amino
      acids in the cerebrospinal fluid from one patient
    explanation: A single human CSF observation weighs against assuming CNS exposure, although it is not decisive.
  proposed_experiments:
  - experiment_id: exp_acy1_human_cns_exposure_response
    name: Human CNS exposure-response validation
    description: >-
      Quantify N-acetylated amino acids in paired plasma and CSF from molecularly
      confirmed cases and test patient-derived neuronal or organoid mitochondrial
      respiration and ATP production at measured concentrations, with isogenic
      ACY1 correction as a rescue control.
- discussion_id: gap_acy1_hearing_replication
  prompt: >-
    Is congenital sensorineural hearing impairment a reproducible human ACY1
    deficiency phenotype, and does the zebrafish auditory-hair-cell mechanism
    translate to the human inner ear?
  kind: HUMAN_MODEL_MISMATCH
  status: OPEN
  attaches_to:
  - pathophysiology#Auditory Hair-Cell Developmental Impairment
  - phenotypes#Congenital sensorineural hearing impairment
  rationale: >-
    The new report combines a single biochemically confirmed human case with a
    zebrafish morpholino phenotype and mRNA rescue. This is stronger than an
    isolated case association but remains vulnerable to single-family,
    morpholino, and cross-species limitations. The authors explicitly require
    additional unrelated patients and independent validation before ACY1 can be
    established as a hereditary hearing-loss gene.
  evidence:
  - reference: PMID:42322530
    reference_title: "A Splice-Site Variant in ACY1 Associated with Congenital Hearing Loss: Clinical, Biochemical, and Zebrafish Functional Evidence."
    supports: SUPPORT
    evidence_source: HUMAN_CLINICAL
    snippet: >-
      Our findings support ACY1 as a candidate gene for hereditary hearing
      impairment, although additional unrelated patients and independent
      validation are needed to further establish the gene-disease relationship.
    explanation: The study authors directly state the candidate-level conclusion and replication requirement.
  proposed_experiments:
  - experiment_id: exp_acy1_hearing_replication
    name: Independent human hearing cohort replication and orthogonal model validation
    description: >-
      Identify unrelated individuals with biallelic ACY1 deficiency and formal
      audiologic phenotyping, then reproduce the hair-cell phenotype in a stable
      acy1 knockout or human inner-ear organoid with wild-type rescue.

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References & Deep Research