
These results are in line with recent evidence highlighting the clinical relevance of D1 antagonists for neuropsychiatric disorders and paving the way for their use in the management of psychotic symptoms in neurodegenerative disorders such as Mucopolysaccharidosis.
Lysosomal storage disorders (LSDs) are rare genetic diseases caused by defects in the function of lysosomes, cellular structures responsible for breaking down substances within the cell.
When these functions fail, certain compounds accumulate in lysosomes, causing progressive damage to cells and tissues throughout the body.
One such disorder is Mucopolysaccharidosis type IIIA-D (MPS-IIIA-D), a serious condition caused by mutations in the SGSH gene, which encodes the enzyme lysosomal sulfamidase. This enzyme is essential for the degradation of heparan sulfate (HS), a type of complex sugar.
When sulfamidase does not work properly, heparan sulfate builds up in the brain and other tissues, causing inflammation, neuron degeneration, and eventually dementia.

Patients diagnosed with mucopolysaccharidosis, a condition that affects one or more enzymes that are essential to the body. Source: HOSPITAL INFANTIL ALBERT SABIN, Photo: Letícia Maia
Most studies on MPS-IIIA have focused on damage to the nervous system and progressive neurological deterioration. However, researchers have identified that this condition can also cause symptoms very similar to those observed in people with Autism Spectrum Disorder (ASD).
Children with MPS-IIIA often present with language delay, social difficulties, repetitive and restricted behavior, and hyperactivity. These symptoms are so common that many patients initially receive a diagnosis of autism before being correctly diagnosed with MPS-IIIA.
In addition, other forms of Mucopolysaccharidosis that accumulate heparan sulfate, such as MPS-I and MPS-II, also present similar behavior patterns.

Mucopolysaccharidosis carriers. Image: Casa Hunter
Treating these symptoms is a major challenge, as medications traditionally used for psychiatric disorders, such as antipsychotics (haloperidol and risperidone) and stimulants (methylphenidate), have proven ineffective in patients with MPS-IIIA.
In addition, these drugs can cause significant side effects, such as tremors and motor difficulties. Thus, finding an effective treatment for the behavioral symptoms of this disease is an urgent medical need.
To better understand the symptoms and seek new therapeutic approaches, researchers at the Telethon Institute of Genetics and Medicine, Italy, used animal models of MPS-IIIA.
They studied genetically modified mice that have mutations in the SGSH gene, mimicking the biochemical and behavioral changes seen in humans with the disease.
From these mice, the scientists analyzed the changes in the brain associated with autistic and dementia symptoms.

The researchers found that early behavioral symptoms, such as hyperactivity and social difficulties, are related to an imbalance in the dopaminergic system, which regulates emotions and movements in the brain.
During the embryonic development of the MPS-IIIA mice, there was an increase in the number of dopaminergic neurons in a brain region called the substantia nigra/ventral tegmental area (SN/VTA).
This increase resulted in an excess of dopamine in the striatum, a part of the brain linked to motor control and behavior. As a result, there was an overactivation of the dopamine D1 pathway (D1R), leading to hyperactive and repetitive behaviors.
In addition, the researchers observed that as the mice aged, the symptoms of hyperactivity and autistic behavior decreased, giving way to dementia-like symptoms, such as memory loss and motor difficulties.
Given this discovery, the scientists formulated a hypothesis: if the problem was an imbalance in the activation of dopamine receptors, a treatment that regulated this signaling could be effective. Thus, they tested different pharmacological approaches to evaluate their effects on hyperactivity and dementia symptoms.
The treatments tested were:
Risperidone: an antipsychotic often used to treat symptoms of autism and hyperactivity. However, the results showed that it did not improve symptoms and even caused unwanted motor side effects in the mice.
Methylphenidate (MPH): a stimulant used to treat ADHD. Although it showed some benefits in reducing neuroinflammation, it did not improve autistic symptoms and even contributed to the progression of dementia symptoms.
Ecopipam: a D1 receptor (D1R) antagonist, which is already used to treat neuropsychiatric disorders such as Tourette Syndrome. Unlike other drugs tested, ecopipam was able to rebalance dopamine signaling, reduce autistic behavioral symptoms, and improve cognition, without worsening neurodegenerative symptoms.
The results of this study provide new evidence that the behavioral symptoms of MPS-IIIA are caused by an overactivation of the dopamine D1 pathway in the brain.

Treatment with D1 receptor antagonists, such as ecopipam, has been shown to be an effective strategy for rebalancing this pathway and alleviating behavioral symptoms without worsening neurodegeneration.
These findings pave the way for clinical trials in humans, and reinforce the importance of D1 antagonists as a possible therapeutic approach for other neuropsychiatric disorders, such as dementia with Lewy bodies.
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D1 dopamine receptor antagonists as a new therapeutic strategy to treat autistic-like behaviours in lysosomal storage disorders
Maria De Risi, Lorenzo Cusimano, Xabier Bujanda Cundin, Mariateresa Pizzo, Ylenia Gigante, Mariagrazia Monaco, Chiara Di Eugenio, and Elvira De Leonibus
Mol Psychiatry (2025).
Abstract:
Lysosomal storage disorders characterized by defective heparan sulfate (HS) degradation, such as Mucopolysaccharidosis type IIIA-D (MPS-IIIA-D), result in neurodegeneration and dementia in children. However, dementia is preceded by severe autistic-like behaviours (ALBs), presenting as hyperactivity, stereotypies, social interaction deficits, and sleep disturbances. The absence of experimental studies on ALBs’ mechanisms in MPS-III has led clinicians to adopt symptomatic treatments, such as antipsychotics, which are used for non-genetic neuropsychiatric disorders. However, they have limited efficacy in MPS-III and lead to higher extrapyramidal effects, leaving ALBs in MPS-IIIA as an unmet medical need with a significant burden on patients and their families. Using mouse and cellular models of MPS-IIIA, we have previously shown that ALBs result from increased proliferation of mesencephalic dopamine neurons during embryogenesis. In adulthood, MPS-IIIA mice exhibit an imbalance of dopaminergic receptor subtypes, resulting in striatal overstimulation of the D1 dopamine receptor (D1R)-direct pathway, contrasting with a downregulation of the D2 dopamine receptor (D2R)-indirect pathway. In this study, we aimed to provide an evidence-based pharmacological approach for managing ALBs in MPS-IIIA. We hypothesized that rebalancing dopaminergic receptor signalling with a D1R antagonist, rather than a D2 antagonist, would lead to safe and effective treatment. Neither risperidone nor methylphenidate improves ALBs in the MPS-IIIA mouse model, with the former showing increased cataleptic (extrapyramidal-like) side effects compared to littermate wild-type animals. Methylphenidate, however, showed some beneficial effects on neuroinflammation and later manifesting dementia-like behaviours. In contrast, ecopipam, a D1 antagonist already used in the clinic for other neuropsychiatric disorders, rescues ALBs, cognition, D1 hyperactivity, and does not worsen neurodegenerative signs. These results align with recent evidence highlighting the clinical relevance of D1 antagonists for neuropsychiatric disorders and pave the way for their use in managing psychotic symptoms in neurodegenerative disorders such as dementia with Lewy bodies.
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