Researchers have identified a rare genetic mutation which occurs in clinical disorders with psychotic features


Treatment for individuals who experience psychosis, such as hallucinations and delusions as a result of psychiatric illness, can be targeted to a specific structural mutation, according to a study published by researchers from McLean Hospital and other institutions in the journalBiological Psychiatry.

The study was led by Deborah L. Levy, Ph.D., director of the Psychology Research Laboratory at McLean Hospital, the largest psychiatric affiliate of Harvard Medical School.

The research provides a proof-of-principle demonstration of symptom relief by targeting a specific genotype and links an individual structural mutation to the pathophysiology of psychosis and treatment response.

In the last decade, significant progress has been made in identifying genetic factors underlying schizophrenia, bipolar disorder, and other psychiatric disorders.

Hundreds if not thousands of common genetic variants are collective risk factors for schizophrenia and other psychotic disorders.

However, the impact of each individual variant is both very small and indecisive in determining risk.

Rare genetic variants, on the other hand, can have large effects on risk.

These variants are thus assumed to impact core pathophysiological processes.

Large-effect mutations are individually rare, with even the most recurrent impacting relatively few individuals.

Some are so rare that they are private mutations, known to occur in only one or a few families, as is the mutation described by Levy and her colleagues.

Levy’s study describes a variant that is characterized by an increase in the number of copies of specific genes (i.e., a copy number variant or CNV).

In this case, is effectively due to the presence of a small extra chromosome. This CNV includes the gene encoding the enzyme glycine decarboxylase (GLDC).

“The compelling aspect is that this CNV can be linked to pathophysiology, and, as the new study shows, to treatment,” said Levy.

GLDC breaks down glycine, which is a co-agonist at the NMDA receptor, a type of excitatory glutamate receptor.

The patients in this study have four, instead of the usual two, copies of the GLDC gene.

“We thus predicted that they would have increased glycine breakdown and thus less glycine available at the glycine modulatory site of the NMDA receptor.

This results in NMDA receptor hypofunction,” said Uwe Rudolph, MD, former director of the Laboratory of Genetic Neuropharmacology at McLean Hospital.

NMDA receptor hypofunction has long been considered an important factor in the pathophysiology of schizophrenia.

Variants in genes associated with NMDA receptor function are overrepresented in schizophrenia.

According to Levy, the presence of an increased number of copies of GLDC raised the question of whether this CNV is medically actionable in individuals with this mutation.

“Starting with individual carriers of the mutation, meaning using a ‘genotype-first’ approach, we sought to determine whether the predicted reduced glycine availability attributable to the increased copy number could be potentially normalized with agents that increase glycine or D-serine availability,” explained Levy.

“This approach contrasts with the usual standard clinical practice of treating individuals on the basis of clinical symptoms or diagnosis independent of specific genetic variants.”

Participants in the study had four identical copies of the GLDC gene.

The authors showed that supplementation of standard psychotropic agents (including clozapine) with glycine or D-cycloserine (a partial selective agonist at the NMDA receptor) resulted in improvement in clinical symptoms.

The researchers provided two independent proof-of-principle demonstrations of symptom relief by targeting this specific genotype.

Notably, the same rare mutation occurred here in different clinical disorders (schizoaffective disorder and bipolar disorder with psychotic features).

This suggests that treatment response was determined by the targeted mutation independently of clinical diagnosis.

“It is important to note that the two subjects studied here bore little clinical resemblance, with distinctly different symptom burdens, and highly dissimilar courses of illness,” noted J. Alexander Bodkin, MD. Bodkin, the director of the Clinical Psychopharmacology Research Program at McLean, oversaw psychiatric care of both subjects throughout the blinded and open-label trials of glycine and d-cycloserine.

“The findings may implicate a ‘molecular subtype’ that may respond to treatments that normalize dysregulation of the glutamatergic system,” said Levy, “Specifically, carriers of other related mutations may potentially benefit from low-dose D-cycloserine as well. If it becomes possible one day to identify patients with such molecular subtypes in clinical practice, studies could be conducted that would potentially make targeted treatment approaches available to a larger group of patients.”

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Researchers at McLean have demonstrated symptom relief in patients within psychosis by targeting a specific genotype. The image is credited to McLean Hospital.

Moreover, one of the study’s authors, Charity J. Morgan, PhD, University of Alabama at Birmingham, stated, “The present study illustrates that targeting structural genetic variants is a promising approach but because these variants are individually rare, most studies will have very small sample sizes, complicating the usual approach to statistical analysis.”

Nevertheless, she said, “Because the effects of a targeted treatment can be large, it is important to prioritize opportunities to study even small groups of patients who may benefit.”

The study was a collaboration of clinicians and researchers from multiple programs at McLean Hospital (including the senior author Deborah L. Levy, PhD, first author J. Alexander Bodkin, MD, James I. Hudson, MD, Laura J. Godfrey, BS, Michael Coleman, MA, Alexander Vuckovic, MD, Joseph T. Coyle, MD, and Uwe Rudolph, MD), Charity J. Morgan, PhD, University of Alabama at Birmingham School of Public Health, James Lupski, MD, PhD, and Claudia M.B. Carvalho, PhD, Baylor College of Medicine, Jonathan Sebat, PhD, University of California at San Diego, and Donald C. Goff, New York University Langone Medical Center.

Niemann-Pick disease type C (NP-C) is a rare autosomal-recessively inherited lysosomal storage disorder. It is caused by mutations in the NPC1 (95%) or NPC2 gene.

It is a progressive and highly heterogeneous disease, characterized by the presentation of visceral, neurological, and psychiatric symptoms.

Apart from the patients that die early from organic failure, most of the patients with juvenile and adolescent/adult onset of the disease, develop neurological and psychiatric symptoms.

In some cases psychiatric signs, mostly psychosis, can be the first sign of the disease. A delay in diagnosis is often seen.

By describing the case of a 16-year old girl, we would like to highlight current opinion about NP-C disease and resume recent findings on the clinical presentation, diagnosis and treatment. We focus on the psychiatric signs, and most important the specific combinations that are typical for the disease.

There is no curative treatment for NP-C. Miglustat is used to modify neurological signs in NP-C.


Niemann-Pick disease type C (NP-C) is a rare autosomal-recessively inherited lysosomal storage disorder. It is caused by mutations in the NPC1 (95%) or NPC2 gene.

The gene-mutations give characteristic abnormalities in the intracellular transport of endocytosed cholesterol with sequestration of unesterified cholesterol in lysosomes and late endosomes. These trafficking defects also cause accumulation of glycosphingolipids in various tissues, including the brain.

The estimated incidence of diagnosis is of 1:100,000-120,000 live births [1,2].

NP-C is a neurovisceral disease, with a highly heterogeneous presentation and is characterized by progressive neurological deterioration and early death. Patients can show visceral, neurological and psychiatric manifestations which present alone or in different combinations [14].

NP-C disorder is chronic, but has a great variation in age of onset and disease course [2,47].

Niemann-Pick type C often remains undetected for many years. There is an average delay in diagnosis of 5–6 years from onset of the neurological symptoms [1,8,9].

The course towards a diagnosis even tends to be longer, when the first presentation is a psychiatric problem [10].

The clinical presentation varies with age at disease onset. It ranges between a rapidly progressive and fatal early onset form, and an adolescent/adult-onset form presenting as a chronic neurodegenerative disease [9].

We can distinguish by onset a pre-/perinatal period (≤3 months), an early infantile form (onset between 3 months of age and 2 years), a late infantile form (onset between 2 – 6 years), a juvenile form (6 – 15 years) and an adolescent/adult onset form (onset from 15 years of age) [1].

Most patients become dependent within a mean delay of 8 years [9] and the majority dies between 10 and 25 years of age [2].

McLean Hospital
Media Contacts: 
Laura Neves – McLean Hospital
Image Source:
The image is credited to McLean Hospital.

Original Research: The study will appear in Biological Psychiatry.


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