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Genetic Disorders That Confer Risk for the Development of Psychosis and White Matter Hyperintensities on T2-weighted Imaging: A Practical Guide for Psychiatrists

  • December 1, 2025
  • Current Issue, Review

Innov Clin Neurosci. 2025;22(10–12):24–32.

by Mark A. Colijn, MD, MSc, FRCPC, UCNS

Dr. Colijn is with the Department of Psychiatry, Mathison Centre for Mental Health Research and Education, and Hotchkiss Brain Institute at the University of Calgary in Calgary, Canada.

FUNDING: No funding was provided for this article.

DISCLOSURES: The author has no conflicts of interest to report regarding the content of this manuscript.

ABSTRACT: Objective: A variety of diseases can cause both psychosis and myelin changes that manifest as white matter hyperintensities on T2-weighted magnetic resonance imaging of the brain. Although many of the acquired conditions relevant to this discussion are widely recognized by psychiatrists and other physicians, a number of lesser-known rare genetic disorders also deserve consideration in this context. As such, this review sought to summarize the phenotypic features, brain imaging abnormalities, and approach to diagnosing the most common leukodystrophies and other genetic leukoencephalopathies that can cause psychosis. Methods: This is a narrative review. The most common leukodystrophies that can cause both psychosis and white matter hyperintensities are first reviewed, followed by a variety of other rarer leukodystrophies and related genetic disorders. Suggestive clinical features, workup recommendations, and potential clinical implications are subsequently discussed. Results: Although the psychotic symptoms that occur in these disorders might phenomenologically resemble those typical of schizophrenia, the identification of any “red flag” neurological features, idiosyncratic medical comorbidities, additional brain imaging abnormalities, parental consanguinity, or a mendelian pattern of inheritance, should prompt consideration for an underlying genetic explanation. Making a correct diagnosis in this context is critical, given the numerous potential clinical implications, including with respect to treatment decisions. Conclusion: While psychiatrists are not expected to be experts in this area, at a minimum they should have a basic familiarity with the genetic disorders that are most likely to cause both psychosis and white matter hyperintensities, given the relatively frequent occurrence of this clinical scenario. Keywords: Neuropsychiatry, leukodystrophy, leukoencephalopathy, psychosis, schizophrenia

Introduction

Although historically there has been variability between guidelines, routine brain imaging is generally not recommended for individuals experiencing a first episode of psychosis, given the low yield of clinically relevant findings.1 However, computed tomography (CT) or magnetic resonance imaging (MRI) of the brain might still be indicated if any “red flag” features suggestive of an underlying neurological cause are present (eg, focal neurological deficits, seizures, unexplained motor abnormalities, autonomic instability, or an abrupt onset of symptoms). Although relatively common and often nonspecific, white matter hyperintensities on T2-weighted MRI should raise suspicion for numerous non-psychiatric etiologies, particularly in younger individuals without vascular risk factors. While the differential is broad and includes a variety of autoimmune/inflammatory conditions (eg, systemic lupus erythematosus, multiple sclerosis, acute disseminated encephalomyelitis), various infectious diseases (eg, human immunodeficiency virus [HIV], syphilis, herpes simplex, Whipple disease), metabolic derangements such as vitamin B12 deficiency, heavy metal poisoning, hepatic encephalopathy, delayed post-hypoxic leukoencephalopathy, and posterior reversible encephalopathy syndrome (regardless of cause), a remarkable number of genetic disorders can also cause both white matter hyperintensities and a constellation of neuropsychiatric symptoms, including psychosis, often beginning as early as childhood. Although the severity and pattern of white matter involvement (in addition to other neuroimaging findings) might in and of itself be suggestive of a particular genetic disorder, this is not always the case. As such, and given that a diagnosis cannot be made based on imaging alone, it is imperative that psychiatrists have at least a general familiarity with the genetic disorders relevant to this discussion to avoid missing or unnecessarily delaying a diagnosis.

This narrative review provides a summary of the genetic disorders most consistently associated with both psychotic symptoms and brain white matter hyperintensities on T2-weighted imaging, while highlighting distinguishing clinical and neuroimaging features, diagnostic testing considerations, and the practical implications of making a correct diagnosis in this context, including with respect to treatment decisions. The most common and well-described leukodystrophies are discussed first, given the inherent and typically prominent white matter lesions that define these diseases, followed by intranuclear inclusion disease, cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL)/cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), and finally a variety of rarer leukodystrophies/leukoencephalopathies and other relevant inborn errors of metabolism for the sake of completeness. The leukodystrophies/leukoencephalopathies most frequently associated with psychotic presentations are summarized in Table 1, including with respect to their clinical features, additional brain imaging abnormalities, and targeted therapies, where available. This review is meant to serve as a resource for psychiatrists who encounter this scenario clinically, given that no such reviews on this topic currently exist.

Specific Genetic Disorders

Common leukodystrophies. The term leukodystrophy refers to a group of variable genetic disorders that result in abnormalities of brain myelin, with two broad categories having been described; demyelinating and hypomyelinating types.2 Although all result in the appearance of white matter hyperintensities on T2-weighted imaging, the specific neuroanatomical pattern of myelin involvement can vary by type.2 Of the most common and well-described leukodystrophies,2 psychotic symptoms have frequently been reported in metachromatic leukodystrophy, adrenoleukodystrophy, vanishing white matter disease, and cerebrotendinous xanthomatosis, as well as in a few cases of Aicardi-Goutières syndrome,3 Alexander disease,4,5 and POLR3-related leukodystrophy.6

Metachromatic leukodystrophy. Metachromatic leukodystrophy is an autosomal recessive inborn error of metabolism caused by pathogenic variants in arylsulfatase A (ARSA).7 Reduced activity of the corresponding enzyme results in accumulation of sulfatides in lysosomes, which is thought in turn to affect intracellular processes involved in myelin maintenance.7 Depending on the specific variants, and by extension the degree of residual enzyme activity, three broad phenotypes exist, including infantile onset, juvenile onset, and adult onset, with psychotic features having been described in the latter two forms. MRI findings typically include diffuse, symmetric periventricular white matter hyperintensities, commonly in a “tigroid” or radial stripe pattern, with more anterior involvement in later onset presentations.7 Clinical features in the later onset forms include some combination of progressive weakness, gait changes, incoordination, abnormal movements, spasticity, seizures, cognitive decline, and behavioral/psychiatric issues.7 In terms of treatment, hematopoietic stem cell transplantation is approved in some countries for certain individuals with pre/early-symptomatic forms of the disease.7

Many reports of psychosis occurring in metachromatic leukodystrophy have been published8–28 with schizophrenia having initially been misdiagnosed in some individuals.8–10,12–19,21,25,28 Commonly reported psychotic symptoms include paranoia8,14,17,19,24 as well as auditory8,10,12–14,18,19,22–24 and visual19,21,23,25,27 hallucinations, in addition to disorganization and manic symptoms in some cases. While antipsychotic therapy (sometimes in combination with other treatments) has led to at least some improvement, psychiatrically speaking, in numerous previously published reports,12,13,19,25–27 a poor response to treatment has also been described in a small number cases.17,18,23

Adrenoleukodystrophy. Adrenoleukodystrophy is an X-linked inborn error of metabolism caused by pathogenic variants in the ABCD1 gene, leading to accumulation of very long chain fatty acids with resultant nervous system and adrenal cortex impairment.29 MRI findings in childhood cerebral adrenoleukodystrophy typically include small T2 hyperintensities within the corpus callosum (splenium or genu), or less commonly the corticospinal tract and cerebellum.29 Clinical phenotypes are variable but typically include some combination of adrenal insufficiency, myeloneuropathy, and cerebral leukodystrophy-related features, such as vision changes, clumsiness, seizures, cognitive decline, and behavioral changes in childhood.29 Hematopoietic stem cell transplantation or gene therapy might be an option for some individuals with cerebral involvement.29

Psychotic symptoms have frequently been reported,30–41 and like in metachromatic leukodystrophy, schizophrenia has often been misdiagnosed early on.32,34–36,38–41 Paranoia32,34,35,38,41 and auditory hallucinations30,32–36,38,41 appear to be common manifestations of psychosis in adrenoleukodystrophy, whereas visual hallucinations have perhaps surprisingly been reported infrequently.35 Disorganization and mania have also commonly been described, with bipolar disorder having been misdiagnosed in numerous cases. While a few individuals have exhibited a good response to antipsychotic therapy,30,31,34 a partial and/or temporary treatment response32,33,35,36,41 or poor response38 have more frequently been reported.

Cerebrotendinous xanthomatosis. Cerebrotendinous xanthomatosis is an autosomal recessive inborn error of metabolism that results from variants in CYP27A1, a gene that encodes an enzyme involved in cholesterol degradation, causing an accumulation of cholestanol and cholesterol throughout the body.42 Brain MRI findings typically include bilateral hyperintensities involving cerebral/cerebellar white matter as well as the dentate nuclei.42 The disease classically involves the development of diarrhea in infancy, childhood-onset cataracts, tendon xanthomas (subcutaneous lipid deposits along tendons) in adolescence or early adulthood, and various neurological problems thereafter, including pyramidal/cerebellar signs/symptoms, atypical Parkinsonism, peripheral neuropathy, seizures, cognitive decline, and psychiatric issues.42 Chenodeoxycholic acid might improve outcomes, particularly if implemented early.42

Psychotic symptoms have been reported in a few individuals43–49 and the disease has rarely been misdiagnosed as schizophrenia.47,48 Although only a few articles have provided information regarding the nature of the psychotic symptoms observed, paranoia,44,46,48 auditory hallucinations,44,48 and visual hallucinations49 have all been reported. Antipsychotic treatment response was reported to be good in two cases,44,49 including in combination with valproate in one,44 and poor in another.46

Vanishing white matter disease. Vanishing white matter disease is an autosomal recessive leukodystrophy caused by variants in one of five genes (EIF2B1–EIF2B5) that encode a subunit of an enzyme involved in ribonucleic acid (RNA) translation, resulting in abnormal astrocytes and oligodendrocytes, and by extension white matter degeneration.50 Brain MRI typically reveals an abnormal signal throughout the cerebral white matter, which can include both hyperintense and hypointense areas, with the possibility of subcortical sparing.50 Rarefaction and cystic degeneration take place over time causing the white matter to “disappear” and have a signal intensity similar to cerebrospinal fluid.50 Childhood and adolescent onset presentations typically involve gradual motor deterioration with prominent ataxia and relative preservation of cognitive functioning, whereas adult-onset cases tend to be more insidious with cognitive decline and variable isolated neurological issues.50 Rapid neurological decline might be triggered by various physical stressors.50 Ovarian failure is also quite common in female individuals.50 No disease-specific treatments currently exist.

Psychotic symptoms have been reported in only a small number of cases,51–55 with few details typically provided; however, paranoia54 and auditory hallucinations53 have been described. No reports of antipsychotic treatment response exist in the literature.

Neuronal intranuclear inclusion disease. Neuronal intranuclear inclusion disease is a repeat expansion disorder that causes increased translation of a neurotoxic protein as a result of NOTCH2NLC involvement.56 Hyperintensities of the cerebral white matter bilaterally on T2-weighted imaging are commonly observed, in addition to increased signal at the corticomedullary boundary on diffusion-weighted-imaging.56 Although variable, symptoms can include cognitive and personality changes as well as muscle weakness, Parkinsonism, ataxia, and autonomic dysfunction.56 While disease progression is often gradual, paroxysmal encephalopathic episodes can occur.56 No specific treatments currently exist.56

Psychotic symptoms have frequently been reported,57–70 and have most often included visual hallucinations,58,60,62,63,65,69,70 whereas auditory hallucinations have only been described in one individual.67 Paranoia69 and various other, albeit often unspecified, delusions have also been reported in numerous cases.58,66–68,70 Only one individual had historically been diagnosed with schizophrenia, and it is not clear if this was related to him having neuronal intranuclear inclusion disease or if rather his remote psychotic symptoms occurred coincidentally.59 A small number of reports have mentioned the use of antipsychotic medication, but with few meaningful details typically provided.58,66,67,69

CADASIL/CARASIL. CADASIL is an autosomal dominant disease due to pathogenic variants in NOTCH3. As NOTCH3 encodes a protein involved in the differentiation and maturation of vascular smooth muscle cells,71 pathogenic variants lead to degeneration of vascular smooth muscle.71 Typical MRI findings include temporal lobe (particularly anteriorly) and external capsule white matter hyperintensities early on, with eventual periventricular and subcortical involvement.71 The phenotype is characterized by the development of migraine with aura, subcortical ischemic events (including transient ischemic attacks and strokes), cognitive decline, and a variety of psychiatric issues, classically in mid-adulthood.71 A related autosomal recessive disorder that is caused by biallelic pathogenic variants in HTRA1, CARASIL, can produce a similar phenotype but classically presents with gait changes consequent to spasticity of the lower extremities.72 No disease-specific treatments currently exist for either condition.

Psychotic symptoms have been reported in both CADASIL73–95 and CARASIL,96–99 and schizophrenia has sometimes been misdiagnosed.73,77,82,98 Psychotic symptoms in CADASIL commonly include paranoia74,76,80,83,85,88,90,94,95 as well as both auditory75,79,80,82,92,94,95 and visual75,76,78–80,84,87,92,94,95 hallucinations. Perhaps surprisingly, given the progressive nature of the disease, numerous individuals have responded well to psychotropic medication regimens that include antipsychotics,79,82,90,91,95 while a poor response has infrequently been described.73,74 Very little information regarding the nature of psychotic symptoms and response to antipsychotic treatment is provided in the papers that described individuals with CARASIL.

Other genetic disorders of potential relevance. Psychotic symptoms have also rarely been described in numerous other leukodystrophies/leukoencephalopathies, such as CLCN2-related leukoencephalopathy,100,101 Labrune syndrome,102 LAMB1-related disorder,103 polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy,104 PUS3-related disorder,105 retinal vasculopathy with cerebral leukoencephalopathy,106,107 Cockayne syndrome,108,109 hereditary diffuse leukoencephalopathy with spheroids,110–114 and megalencephalic leukoencephalopathy with subcortical cysts.115–117

Additionally, a variety of inborn errors of metabolism not classified as leukodystrophies/leukoencephalopathies can nonetheless sometimes cause variable white matter hyperintensities (in addition to other abnormal brain imaging findings) as well as psychosis. The most obvious examples include different types of homocystinuria, urea cycle disorders, phenylketonuria, succinic semialdehyde dehydrogenase (SSADH) deficiency, maple syrup urine disease, Wilson disease, and mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), as well as numerous lysosomal storage disorders, such as Niemann Pick type C, Tay-Sachs disease, neuronal ceroid lipofuscinosis, and alpha mannosidosis.118

When to suspect one of these disorders

Although it is unrealistic to expect general psychiatrists to have a comprehensive knowledge of every disorder described here, clinicians providing care for schizophrenia populations should at least have a general awareness that these diseases exist to ensure their consideration when atypical clinical presentations are encountered in this context. Specifically, after acquired etiologies of relevance have been ruled out, numerous “red flag” features should prompt consideration for a leukodystrophy or related disorder. Although the nature of the psychotic symptoms themselves might resemble those observed in “idiopathic” schizophrenia, unusually episodic or progressive phenotypes should raise suspicion for one of these conditions, as should the cooccurrence of ataxia, Parkinsonism, dyskinetic movements, spasticity, seizures, focal neurological deficits, or cognitive impairment that is more pronounced (or cognitive decline that is more rapid) than is typical of a primary psychotic disorder.

Additionally, some of the aforementioned disorders have unique or idiosyncratic clinical features that should heighten one’s suspicion for a particular genetic etiology. For example, as mentioned, childhood onset cataracts and tendon xanthomas commonly occur in cerebrotendinous xanthomatosis, adrenal insufficiency in adrenoleukodystrophy, ovarian failure in vanishing white matter disease, and strokes in CADASIL/CARASIL. Acquired microcephaly, sterile pyrexias, hepatosplenomegaly, and chilblain lesions of the hands, feet, and ears can occur in Aicardi-Goutières syndrome,119 dental anomalies, endocrine abnormalities (in particular hypogonadism), and progressive myopia in POLR3-related leukodystrophy,120 vision/hearing loss and male infertility in CLCN2-related leukoencephalopathy,100 cystic osseous lesions and fractures of the wrists and ankles as well as the carpal and tarsal bones in polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy,121 vascular retinopathy as well as microvascular liver and renal disease in retinal vasculopathy with cerebral leukoencephalopathy,122 growth failure and progressive microcephaly in Cockayne syndrome,123 skeletal abnormalities and dysmorphic features as well as anopsias in hereditary diffuse leukoencephalopathy with spheroids,124 and macrocephaly in megalencephalic leukoencephalopathy with subcortical cysts.125

Additional “red flags” include parental consanguinity, given that many of these disorders are autosomal recessive in nature, as well as other Mendelian patterns of inheritance with respect to neuropsychiatric phenotypes (eg, X-linked in the case of adrenoleukodystrophy and autosomal dominant in the case of CADASIL). However, as the variants in question might occur de novo, the absence of a suggestive family history should not be taken as evidence that an individual does not have a given disorder.

In addition to causing myelin changes that manifest as white matter hyperintensities on imaging, many of these disorders are also associated with additional, sometimes highly specific, brain imaging findings. These include, as mentioned, rarefaction and cystic degeneration of white matter in vanishing white matter disease,50 calcifications, striatal necrosis, and various intracerebral vasculopathies (eg, aneurysms, moyamoya) in Aicardi-Goutières syndrome,119 lacunes and cerebral microbleeds in CADASIL/CARASIL,71,72 calcifications and cysts in Labrune syndrome,126 basal ganglia calcifications on CT in polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy,121 hyperintense mass lesions in retinal vasculopathy with cerebral leukoencephalopathy,122 calcifications, Dandy-Walker malformation, and/or malformations of cortical development in hereditary diffuse leukoencephalopathy with spheroids,124 and cerebral white matter swelling and subcortical cysts in megalencephalic leukoencephalopathy with subcortical cysts.125 Cerebral and/or cerebellar atrophy might also occur over time in many of the disorders.

Workup Recommendations

Although a number of biochemical screening tests exist for some of the aforementioned disorders, confirmatory testing for most requires the use of gene panels, targeted sequencing, or whole genome/exome sequencing. While psychiatrists might be able to order some relevant biochemical screens (depending on location), diagnostic testing to confirm a given pathogenic variant typically requires the involvement of medical genetics.

Screening for metachromatic leukodystrophy involves testing Arylsulfatase A enzyme activity in leukocytes, which is reduced in the disease; however, decreased activity might also reflect pseudodeficiency in unaffected individuals.7 Establishing the diagnosis requires the identification of biallelic pathogenic ARSA variants, increased urinary sulfatides, or metachromatic lipid deposits in biopsy derived nervous system tissue.7 Adrenoleukodystrophy is screened for via very long chain fatty acid testing in the serum or plasma, and the diagnosis is confirmed by identifying a hemizygous (given that the disease is X-linked) pathogenic ABCD1 variant in male individuals or a heterozygous pathogenic variant in female individuals.29 Cerebrotendinous xanthomatosis is suggested by a high concentration of plasma and tissue cholestanol and a high concentration of plasma and urine bile alcohols, while the diagnosis is confirmed by identifying biallelic pathogenic CYP27A1 variants.42 Although cerebrospinal fluid glycine levels might be elevated, there are no recommended screening tests for vanishing white matter disease, and the diagnosis is established by identifying biallelic pathogenic variants in one of five genes (EIF2B1–EIF2B5).50 There are no biochemical screening tests for any of the other leukodystrophies/leukoencephalopathies mentioned, and genetic testing is required to make a diagnosis in all cases, except for polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy,121 Cockayne syndrome,123 and megalencephalic leukoencephalopathy with subcortical cysts,125 where a diagnosis can alternatively be made on clinical grounds alone. Although biochemical screening tests are available for many of the other inborn errors of metabolism mentioned (that are not classified as leukodystrophies), a comprehensive review of these disorders is beyond the scope of this manuscript.

Clinical Implications

Given that psychosis might be a presenting symptom in some of these diseases in a minority of cases, affected individuals might first come to the attention of mental health services. As such, it is imperative that psychiatrists consider these diseases when encountering schizophrenia-like presentations that occur in association with brain white matter hyperintensities on imaging.

Early diagnosis is critical for numerous reasons. First, making the correct diagnosis might allow for earlier identification and management (even if only supportive) of other medical problems predisposed to by a given genetic disorder. Second, and perhaps most notably, targeted therapies exist for some of these conditions, including, as mentioned, hematopoietic stem cell transplantation in metachromatic leukodystrophy7 and adrenoleukodystrophy,29 and chenodeoxycholic acid in cerebrotendinous xanthomatosis.42 Additional examples include the potential utility of hematopoietic stem cell transplantation in CSF1R-related disorder (which includes hereditary diffuse leukoencephalopathy with spheroids),124 vitamin B6, B9, and B12 supplementation as well as betaine therapy in homocystinuria,127 and some combination of sodium phenylacetate/sodium phenylbutyrate/sodium benzoate, L-arginine, L-citrulline, and N-carbamoylglutamate in urea cycle disorders (depending on the particular type).128 In the acute phase of urea cycle disorders, hemodialysis/hemodiafiltration can rapidly lower ammonia levels, and liver transplantation early in life (which is curable) might be available to some patients.128 Liver transplantation can similarly prevent metabolic crises but does not reverse preexisting neuropsychiatric deficits in maple syrup urine disease.129 Coenzyme Q10, L-carnitine, and creatine might provide benefit to some individuals with MELAS, while intravenous arginine is used during acute stroke-like episodes and prophylactically thereafter to reduce the risk of recurrence.130 Sapropterin dihydrochloride, a phenylalanine hydroxylase activator/cofactor and the phenylamine metabolizing enzyme, pegvaliase, might be indicated in some individuals with phenylketonuria.131 Copper chelating compounds (eg, penicillamine) followed by zinc therapy are used in Wilson disease, in addition to liver transplantation in individuals who fail to respond to, or who cannot tolerate medications.132 In some countries, miglustat is approved for use in Niemann Pick type C,133 cerliponase alfa in neuronal ceroid lipofuscinosis type 2,134 and velmanase alfa in alpha mannosidosis.135

Relatedly, some treatments are at least relatively contraindicated because of their compounding effects on disease pathophysiology; for example, concerns exist with respect to the use of statins in cerebrotendinous xanthomatosis,42 thrombolytic therapy/oral anticoagulants in CADASIL,71 metronidazole in Cockayne syndrome,123 oral contraceptives and surgery in homocystinuria,127 valproate and corticosteroids in urea cycle disorders,128 a variety of medications in mitochondrial disorders such as MELAS, including valproate and metformin,130 aspartame-containing medications in phenylketonuria,131 and arguably vigabatrin, tiagabine, and valproate in SSADH deficiency.136

Some of the inborn errors of metabolism also have dietary recommendations; for example, a methionine-restricted diet in homocystinuria,127 a protein-restricted diet with high caloric intake in urea cycle disorders,128 a low phenylalanine diet in phenylketonuria in addition to phenylalanine free protein supplementation with medical foods,131 a branched-chain amino acid restricted diet in maple syrup urine disease,129 and a copper-restricted diet in Wilson disease.132

While the use of targeted therapies and the formulation of dietary recommendations are generally overseen by multidisciplinary genetics/metabolics services, diagnosing one of these disorders might also influence decisions with respect to the selection of antipsychotic medications (which, as outlined above, may be effective for some individuals) based on potential medical comorbidities. For example, in patients who have (or are at risk of developing) seizures, especially seizurogenic antipsychotics (eg, clozapine) should probably be avoided, if possible. Similarly, the more potent D2 receptor antagonists might be poorly tolerated among patients likely to develop Parkinsonism, while highly anticholinergic antipsychotics might compound cognitive problems in diseases that cause dementia. As many of the disorders discussed confer risk for all of these problems, clinical judgement is required on a case-by-case basis, taking into account which neurological comorbidities are (or are likely to be) most severe/disabling.

It is also important that psychiatrists have a reasonable understanding of a given disease’s trajectory and prognosis when encountered clinically, not only for the sake of appropriately educating patients, but also for their own understanding of disease progression as it pertains to the clinical management of patients. In particular, as neurological deterioration takes place there can be a gradual worsening of psychiatric symptoms, with a poorer response to treatment and a heightened sensitivity to antipsychotic-induced side effects.

Lastly, making a correct diagnosis in this context should allow for an individual and their family to access genetic counseling supports, a critical component of the care provided to patients with rare genetic disorders.

Conclusion

The identification of white matter hyperintensities on T2-weighted brain imaging in individuals experiencing psychosis should prompt consideration for a variety of genetic etiologies in the absence of other explanations, particularly if other suggestive features are present. Although some psychiatrists might feel comfortable initiating a preliminary screening workup for certain inborn errors of metabolism, when in doubt it is recommended that medical genetics be consulted, particularly given that for most of the diseases discussed a diagnosis can only be confirmed with the use of gene panels, targeted sequencing, or whole genome/exome sequencing. Making a correct diagnosis in this context can have important clinical implications, including with respect to treatment decisions.

References

  1. Forbes M, Stefler D, Velakoulis D, et al. The clinical utility of structural neuroimaging in first-episode psychosis: A systematic review. Aust N Z J Psychiatry. 2019;53(11):1093–1104.
  2. Adang L. Leukodystrophies. Continuum (Minneap Minn). 2022;28(4):1194–1216.
  3. Arroyo-Andres J, Arteche-Lopez AR, Gonzalez-Granado I, et al. Pseudo-catatonia and acral degos-like lesions: an atypical form of the Aicardi-Goutieres syndrome. Actas Dermosifiliogr. 2024;115(10):1045–1046.
  4. Elmali AD, Cetincelik U, Islak C, et al. Familial adult-onset Alexander Disease: clinical and neuroradiological findings of three cases. Noro Psikiyatr Ars. 2016;53(2):169–172.
  5. Fu MH, Chang YY, Lin NH, et al. Recessively-inherited adult-onset Alexander disease caused by a homozygous mutation in the GFAP gene. Mov Disord. 2020;35(9):1662–1667.
  6. D’Souza O, Rashidianfar A. A case report of POL3A leukodystrophy presenting with first episode psychosis. Australas Psychiatry. 2024;32(3):259.
  7. Gomez-Ospina N. Arylsulfatase A Deficiency. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993.
  8. Betts TA, Smith WT, Kelly RE. Adult metachromatic leukodystrophy (sulphatide lipidosis) simulating acute schizophrenia. Report of a case. Neurology. 1968;18(11):1140–1142.
  9. Suzuki C, Watanabe M, Tomiyama M, et al. A novel mutation in the arylsulfatase A gene associated with adult-onset metachromatic leukodystrophy without clinical evidence of neuropathy. Eur Neurol. 2008;60(6):310–311.
  10. Baumann N, Turpin JC, Lefevre M, et al. Motor and psycho-cognitive clinical types in adult metachromatic leukodystrophy: genotype/phenotype relationships? J Physiol Paris. 2002;96(3-4):301–316.
  11. Lugowska A, Berger J, Tylki-Szymanska A, et al. Molecular and phenotypic characteristics of metachromatic leukodystrophy patients from Poland. Clin Genet. 2005;68(1):48–54.
  12. Kumperscak HG, Paschke E, Gradisnik P, et al. Adult metachromatic leukodystrophy: disorganized schizophrenia-like symptoms and postpartum depression in 2 sisters. J Psychiatry Neurosci. 2005;30(1):33–36.
  13. Kumperscak HG, Plesnicar BK, Zalar B, et al. Adult metachromatic leukodystrophy: a new mutation in the schizophrenia–like phenotype with early neurological signs. Psychiatr Genet. 2007;17(2):85–91.
  14. Besson JA. A diagnostic pointer to adult metachromatic leucodystrophy. Br J Psychiatry. 1980;137:186–7.
  15. Rauschka H, Colsch B, Baumann N, et al. Late-onset metachromatic leukodystrophy: genotype strongly influences phenotype. Neurology. 2006;67(5):859–863.
  16. Fukutani Y, Noriki Y, Sasaki K, et al. Adult-type metachromatic leukodystrophy with a compound heterozygote mutation showing character change and dementia. Psychiatry Clin Neurosci. 1999;53(3):425–428.
  17. Finelli PF. Metachromatic leukodystrophy manifesting as a schizophrenic disorder: computed tomographic correlation. Ann Neurol. 1985;18(1):94–95.
  18. Waltz G, Harik SI, Kaufman B. Adult metachromatic leukodystrophy. Value of computed tomographic scanning and magnetic resonance imaging of the brain. Arch Neurol. 1987;44(2):225–227.
  19. Manowitz P, Kling A, Kohn H. Clinical course of adult metachromatic leukodystrophy presenting as schizophrenia. A report of two living cases in siblings. J Nerv Ment Dis. 1978;166(7):500–506.
  20. Cappell MS, Marks M, Kirschenbaum H. Massive hemobilia and acalculous cholecystitis due to benign gallbladder polyp. Dig Dis Sci. 1993;38(6):1156–1161.
  21. Miura A, Kumabe Y, Kimura E, et al. Diffusion and ADC-map images detect ongoing demyelination on subcortical white matter in an adult metachromatic leukodystrophy patient with autoimmune Hashimoto thyroiditis. BMJ Case Rep. 2010;2010.
  22. Wulff CH, Trojaborg W. Adult metachromatic leukodystrophy: neurophysiologic findings. Neurology. 1985;35(12):1776–1778.
  23. Tunalı H, Ünal S, Acar C, et al. A case of adult-onset metachromatic leukodystrophy beginning with behavioral symtoms. J Clinical Psychiatry. 2023;26(1):69–75.
  24. Chee KY, Azize NAA, Zain NRM, et al. Adult-onset metachromatic leukodystrophy with compound heterozygous ARSA gene mutation presented with mania and cognitive decline. Neurology Asia. 2016;21(2):199–201.
  25. Filley CM, Gross KF. Psychosis in neurologic diseases psychosis with cerebral white matter disease. Neuropsychiatry, Neuropsychology and Behavioral Neurology. 1992;5(2):119–125.
  26. Sadeh M, Kuritzky A, Ben-David E, et al. Adult metachromatic leukodystrophy with an unusual relapsing-remitting course. Postgrad Med J. 1992;68(797):192–195.
  27. Ben Ammar H, Hakiri A, Khelifa E, et al. Metachromatic leukodystrophy presenting as a bipolar disorder: a case report. Encephale. 2022;48(1):108–109.
  28. Colsch B, Afonso C, Turpin JC, et al. Sulfogalactosylceramides in motor and psycho-cognitive adult metachromatic leukodystrophy: relations between clinical, biochemical analysis and molecular aspects. Biochim Biophys Acta. 2008;1780(3):434–440.
  29. Raymond GV, Moser AB, Fatemi A. X-Linked Adrenoleukodystrophy. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993.
  30. Chee KY, Ong BH, Kartikasalwah AL, et al. Bipolar I disorder presaging X-linked adrenoleukodystrophy. J Neuropsychiatry Clin Neurosci. 2013;25(3):E20–22.
  31. Gothelf D, Levite R, Gadoth N. Bipolar affective disorder heralding cerebral demyelination in adreno-myelo-leukodystrophy. Brain Dev. 2000;22(3):184–187.
  32. Menza MA, Blake J, Goldberg L. Affective symptoms and adrenoleukodystrophy: a report of two cases. Psychosomatics. 1988;29(4):
    442–445.
  33. Ramos-Rios R, Berdullas J, Arauxo A, et al. Schizophreniform psychosis at onset of adrenoleukodystrophy. CNS Spectr. 2009;14(12):711–712.
  34. Furuhashi Y, Ishikawa M. Adult-onset adrenoleukodystrophy heralded by auditory hallucinations and delusions. Psychosomatics. 2011;52(5):492–493.
  35. Garside S, Rosebush PI, Levinson AJ, et al. Late-onset adrenoleukodystrophy associated with long-standing psychiatric symptoms. J Clin Psychiatry. 1999;60(7):460–468.
  36. Shamim D, Alleyne K. X-linked adult-onset adrenoleukodystrophy: Psychiatric and neurological manifestations. SAGE Open Med Case Rep. 2017;5:2050313X17741009.
  37. Jiang W, Jin W, Zhao H, et al. Initial frontal lobe involvement in adult cerebral X-linked adrenoleukodystrophy. Acta Neurol Belg. 2023;123(6):2259–2268.
  38. Makkar H, Corona CC, Wadhawan A, et al. Adult-cerebral X-linked adrenoleukodystrophy: a mirage of psychosis, mania, and substance use. Psychiatric Annals. 2020;50(9):417–420.
  39. Angus B, de Silva R, Davidson R, et al. A family with adult-onset cerebral adrenoleucodystrophy. J Neurol. 1994;241(8):497–499.
  40. Panegyres PK, Goldswain P, Kakulas BA. Adult-onset adrenoleukodystrophy manifesting as dementia. Am J Med. 1989;87(4):481–483.
  41. James AC, Kaplan P, Lees A, et al. Schizophreniform psychosis and adrenomyeloneuropathy. J R Soc Med. 1984;77(10):882–884.
  42. Federico A, Gallus GN. Cerebrotendinous Xanthomatosis. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993.
  43. Fraidakis MJ. Psychiatric manifestations in cerebrotendinous xanthomatosis. Transl Psychiatry. 2013;3(9):e302.
  44. Ling CX, Gao SZ, Li RD, et al. Cerebrotendinous xanthomatosis presenting with schizophrenia-like disorder: a case report. World J Psychiatry. 2023;13(11):967–972.
  45. Atallah I, Millan DS, Benoit W, et al. Spinal cerebrotendinous xanthomatosis: a case report and literature review. Mol Genet Metab Rep. 2021;26:100719.
  46. Kaloglu HA, Nazli SB. Journey to diagnosis with a rare neurometabolic disease, cerebrotendinus xantomatosis (Van Bogaert disease) and concomitant psychiatric symptoms. Psychiatr Danub. 2023;35(2):263–265.
  47. Khouj E, Bohlega S, Alkuraya FS. Cerebrotendinous xanthomatosis: A candidate for ACMG list of secondary findings? Clin Genet. 2023;103(1):125–126.
  48. Lee CW, Lee JJ, Lee YF, et al. Clinical and molecular genetic features of cerebrotendinous xanthomatosis in Taiwan: report of a novel CYP27A1 mutation and literature review. J Clin Lipidol. 2019;13(6):954–959.
  49. Giraldo-Chica M, Acosta-Baena N, Urbano L, et al. Novel cerebrotendinous xanthomatosis mutation causes familial early dementia in Colombia. Biomedica. 2015;35(4):563–571.
  50. van der Knaap MS, Bugiani M, Abbink TEM. Vanishing white matter. Handb Clin Neurol. 2024;204:77–94.
  51. Klingelhoefer L, Misbahuddin A, Jawad T, et al. Vanishing white matter disease presenting as opsoclonus myoclonus syndrome in childhood—a case report and review of the literature. Pediatr Neurol. 2014;51(1):157–164.
  52. Ohtake H, Shimohata T, Terajima K, et al. Adult-onset leukoencephalopathy with vanishing white matter with a missense mutation in EIF2B5. Neurology. 2004;62(9):1601–1603.
  53. Denier C, Orgibet A, Roffi F, et al. Adult-onset vanishing white matter leukoencephalopathy presenting as psychosis. Neurology. 2007;68(18):1538–1539.
  54. van der Knaap MS, Leegwater PAJ, van Berkel CGM, et al. Arg113His mutation in eIF2Bε as cause of leukoencephalopathy in adults. Neurology. 2004;62(9):1598–1600.
  55. Labauge P, Horzinski L, Ayrignac X, et al. Natural history of adult-onset eIF2B-related disorders: a multicentric survey of 16 cases. Brain. 2009;132(Pt 8):2161–2169.
  56. Zhang T, Bao L, Chen H. Review of phenotypic heterogeneity of neuronal intranuclear inclusion disease and NOTCH2NLC-related GGC repeat expansion disorders. Neurol Genet. 2024;10(2):e200132.
  57. Shen Y, Jiang K, Liang H, et al. Encephalitis-like episodes with cortical edema and enhancement in patients with neuronal intranuclear inclusion disease. Neurol Sci. 2024;45(9):4501–4511.
  58. Ge R, Li K, Xu J, et al. Adult-onset neuronal intranuclear inclusion disease presenting with acute encephalitis-like episode and without characteristic hyperintensities on MR-DWI: a case report. Neurol Sci. 2024;45(10):
    5091–5096.
  59. Zhang T, Chancellor A, Liem B, et al. Neuronal intranuclear inclusion disease in New Zealand: a novel discovery. J Neurol Sci. 2024;460:122987.
  60. Zhou Q, Tian M, Yang H, et al. Adult-onset neuronal intranuclear inclusion disease with mitochondrial encephalomyopathy, lactic acidosis, and strokelike (MELAS-like) episode: a case report and review of literature. Brain Sci. 2022;12(10):1377.
  61. Liu YH, Chou YT, Chang FP, et al. Neuronal intranuclear inclusion disease in patients with adult-onset non-vascular leukoencephalopathy. Brain. 2022;145(9):3010–3021.
  62. Moran JMT, Eikermann-Haerter K, Rapalino O, et al. Cutaneous findings of sporadic, adult-onset neuronal intranuclear inclusion disease. Am J Dermatopathol. 2022;44(1):1–6.
  63. Zhao D, Zhu S, Xu Q, et al. Neuronal intranuclear inclusion disease presented with recurrent vestibular migraine-like attack: a case presentation. BMC Neurol. 2021;21(1):334.
  64. Tachi K, Takata T, Kume K, et al. Long-term MRI findings of adult-onset neuronal intranuclear inclusion disease. Clin Neurol Neurosurg. 2021;201:106456.
  65. Dong H, Ji G, Liu P, et al. A case of adult-onset neuronal intranuclear inclusion disease without abnormal high-intensity signal in the corticomedullary junction in diffusion-weighted imaging. Neurol Sci. 2020;41(9):2653–2655.
  66. Cupidi C, Dijkstra AA, Melhem S, et al. Refining the spectrum of neuronal intranuclear inclusion disease: a case report. J Neuropathol Exp Neurol. 2019;78(7):665–670.
  67. Kawarabayashi T, Nakamura T, Seino Y, et al. Disappearance of MRI imaging signals in a patient with neuronal intranuclear inclusion disease. J Neurol Sci. 2018;388:1–3.
  68. Sugiyama A, Sato N, Kimura Y, et al. MR imaging features of the cerebellum in adult-onset neuronal intranuclear inclusion disease: 8 cases. AJNR Am J Neuroradiol. 2017;38(11):2100–2104.
  69. Shrimpton M, Gasser YP, Sexton A, et al. Episodic headaches and cognitive decline: uncovering neuronal intranuclear inclusion disease in a young patient. BMJ Case Rep. 2025;18(1):e262351.
  70. Katayama T, Takahashi K, Yahara O, et al. NOTCH2NLC mutation-positive neuronal intranuclear inclusion disease with retinal dystrophy: a case report and literature review. Medicine (Baltimore). 2023;102(19):e33789.
  71. Hack RJ, Rutten J, Lesnik Oberstein SAJ. Cadasil. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993.
  72. Onodera O, Nozaki H, Fukutake T. HTRA1 Disorder. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993.
  73. Maroney Z, Dale R. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL): a rare diagnosis in a patient with schizophrenia. Psychosomatics. 2020;61(4):395–399.
  74. Mishra DK, Kishore A, Niranjan V. CADASIL syndrome (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) presenting as psychosis. Gen Psychiatr. 2018;31(3):e100017.
  75. Torres M, Hamby T, Tilley J, et al. Three pediatric siblings with CADASIL. Pediatr Neurol. 2022;129:31–36.
  76. Drazyk AM, Tan RYY, Tay J, et al. Encephalopathy in a large cohort of British cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy patients. Stroke. 2019;50(2):283–290.
  77. Nicolas G, Beherec L, Hannequin D, et al. Dementia in middle-aged patients with schizophrenia. J Alzheimers Dis. 2014;39(4):809–822.
  78. Nakamura T, Watanabe H, Hirayama M, et al. CADASIL with NOTCH3 S180C presenting anticipation of onset age and hallucinations. J Neurol Sci. 2005;238(1–2):87–91.
  79. Ho CS, Mondry A. CADASIL presenting as schizophreniform organic psychosis. Gen Hosp Psychiatry. 2015;37(3):273 e11–13.
  80. Sari US, Kisabay A, Batum M, et al. CADASIL with atypical clinical symptoms, magnetic resonance imaging, and novel mutations: two case reports and a review of the literature. J Mol Neurosci. 2019;68(4):529–538.
  81. Verin M, Rolland Y, Landgraf F, et al. New phenotype of the cerebral autosomal dominant arteriopathy mapped to chromosome 19: migraine as the prominent clinical feature. J Neurol Neurosurg Psychiatry. 1995;59(6):
    579–585.
  82. Lagas PA, Juvonen V. Schizophrenia in a patient with cerebral autosomally dominant arteriopathy with subcortical infarcts and leucoencephalopathy (CADASIL disease). Nord J Psychiatry. 2001;55(1):41–42.
  83. Filley CM, Thompson LL, Sze CI, et al. White matter dementia in CADASIL. J Neurol Sci. 1999;163(2):163–167.
  84. Gueremy A, Felician O, Wenisch E, et al. Cortical type memory impairment in CADASIL: Watch out for the second train! Rev Neurol (Paris). 2024;180(8):835–837.
  85. Aghetti A, Amsellem T, Herve D, et al. Border-zone cerebral infarcts associated with COVID-19 in CADASIL: a report of 3 cases and literature review. Cerebrovasc Dis Extra. 2024;14(1):1–8.
  86. Nogueira R, Couto CM, Oliveira P, et al. Clinical and epidemiological profiles from a case series of 26 Brazilian CADASIL patients. Arq Neuropsiquiatr. 2023;81(5):417–425.
  87. Ferrante E, Trimboli M, Erminio C, et al. Acute confusional migraine in CADASIL: A case report and literature review. Clin Neurol Neurosurg. 2022;216:107239.
  88. MacDonald A, Alvaro A. CADASIL in a patient with bilateral internal carotid artery agenesis. J Clin Neurosci. 2021;83:128–130.
  89. Velayudhan AM, Chandran JR, Jayasree S, et al. Pregnancy and delivery in a patient with CADASIL: a case report. J South Asian Feder Obst Gynae. 2020;12(5):326–327.
  90. Uppal M, Kanellopoulos D, Kotbi N. CADASIL presenting as late-onset mania with anosognosia. Clin Case Rep. 2020;8(1):47–50.
  91. Bangash A, Saad K. Bipolar disorder against a background of a rare vascular dementia. Progress in Neurology and Psychiatry. 2016;20(3):10–12.
  92. Dericioglu N, Vural A, Agayeva N, et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) in two siblings with neuropsychiatric symptoms. Psychosomatics. 2013;54(6):
    594–598.
  93. Tfelt-Hansen P, Thorbjorn Jensen L, Olesen J. Delayed hyperperfusion following migraine with a prolonged aphasic aura in a patient with CADASIL. Cephalalgia. 2008;28(8):899–902.
  94. Paraskevas GP, Bougea A, Synetou M, et al. CADASIL and autoimmunity: coexistence in a family with the R169C mutation at exon 4 of the NOTCH3 gene. Cerebrovasc Dis. 2014;38(4):302–307.
  95. Paraskevas GP, Constantinides VC, Bougea A, et al. Cerebral autosomal dominant arteriopathy with subcortical infarcts and leucoancepahlopathy presenting with postpartum psychosis and late-onset stroke. Future Neurology. 2016;11(3):207–213.
  96. Al Nidawi F, Wael M, Alkhater N, et al. When recurrent strokes, back pain, and alopecia constitute a hereditary cause of small-vessel disease, CARASIL in an Arabic woman. Neurologist. 2023;28(4):262–265.
  97. Lee YC, Chung CP, Chao NC, et al. Characterization of heterozygous HTRA1 mutations in Taiwanese patients with cerebral small vessel disease. Stroke. 2018;49(7):
    1593–1601.
  98. Devaraddi N, Jayalakshmi G, Mutalik NR. CARASIL, a rare genetic cause of stroke in the young. Neurol India. 2018;66(1):232–234.
  99. Menezes Cordeiro I, Nzwalo H, Sa F, et al. Shifting the CARASIL paradigm: report of a non-Asian family and literature review. Stroke. 2015;46(4):1110–1112.
  100. Min R, Depienne C, Sedel F, et al. CLCN2-related leukoencephalopathy. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993.
  101. Depienne C, Bugiani M, Dupuits C, et al. Brain white matter oedema due to ClC-2 chloride channel deficiency: an observational analytical study. Lancet Neurol. 2013;12(7):659–668.
  102. Sim CY, Mukari SAM, Ngu LH, et al. Labrune’s syndrome presenting with stereotypy-like movements and psychosis: a case report and review. J Mov Disord. 2022;15(2):162–166.
  103. Morel H, Bailly L, Urbanczyk C, et al. Extension of the clinicoradiologic spectrum of newly described end-truncating LAMB1 variations. Neurol Genet. 2023;9(3):e200069.
  104. Kobayashi K, Kobayashi E, Miyazu K, et al. Hypothalamic haemorrhage and thalamus degeneration in a case of Nasu-Hakola disease with hallucinatory symptoms and central hypothermia. Neuropathol Appl Neurobiol. 2000;26(1):98–101.
  105. de Paiva ARB, Lynch DS, Melo US, et al. PUS3 mutations are associated with intellectual disability, leukoencephalopathy, and nephropathy. Neurol Genet. 2019;5(1):e306.
  106. Wang X, Su Li, Han J, et al. Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations in conjunction with systemic lupus erythematosus: Missed diagnosis or misdiagnosis? Immun Inflamm Dis. 2024;12(8):e1367.
  107. DiFrancesco JC, Novara F, Zuffardi O, et al. TREX1 C-terminal frameshift mutations in the systemic variant of retinal vasculopathy with cerebral leukodystrophy. Neurol Sci. 2015;36(2):323–330.
  108. Cho S, Traboulsi EI, Chiang J, et al. Multimodal imaging in a family with Cockayne syndrome with a novel pathogenic mutation in the ERCC8 gene, and significant phenotypic variability. Doc Ophthalmol. 2020;141(1):89–97.
  109. Cheng H, Chen D, Wu Z, et al. Atypical features in two adult patients with Cockayne syndrome and analysis of genotype-phenotype correlation. Chin Med J (Engl). 2023;136(17):2110–2112.
  110. Yokote A, Ouma S, Takahashi K, et al. [A case of hereditary diffuse leukoencephalopathy with spheroids and pigmented glia presenting with long–term mild psychiatric symptoms]. Rinsho Shinkeigaku. 2020;60(6):420–424.
  111. Sharma R, Graff-Radford J, Rademakers R, et al. CSF1R mutation presenting as dementia with Lewy bodies. Neurocase. 2019;25(1–2):17–20.
  112. Traschutz A, Hattingen E, Klockgether T, et al. Mirror movements and blepharoclonus as novel phenomena in hereditary diffuse leukoencephalopathy with spheroids. Parkinsonism Relat Disord. 2019;58:83–84.
  113. Shu Y, Long L, Liao S, et al. Involvement of the optic nerve in mutated CSF1R-induced hereditary diffuse leukoencephalopathy with axonal spheroids. BMC Neurology. 2016;16(1).
  114. Kawakami I, Iseki E, Kasanuki K, et al. A family with hereditary diffuse leukoencephalopathy with spheroids caused by a novel c.2442+2T>C mutation in the CSF1R gene. J Neurol Sci. 2016;367:349–355.
  115. Avsar PA, Akcay E, Gurkas E. Psychotic attack during the clinical course of megalencephalic leukoencephalopathy with subcortical cysts: a case report. Eur Child Adolesc Psychiatry. 2025;34(3):1075–1080.
  116. Kaushal H, Khutan H, Sood H, et al. Van Der Knaap disease: young male with megalencephalic leukoencephalopathy with subcortical cysts: a case report. Neurol India. 2022;70(6):2437–2439.
  117. Mancini C, Vaula G, Scalzitti L, et al. Megalencephalic leukoencephalopathy with subcortical cysts type 1 (MLC1) due to a homozygous deep intronic splicing mutation (c.895–226T>G) abrogated in vitro using an antisense morpholino oligonucleotide. Neurogenetics. 2012;13(3):205–214.
  118. Trakadis YJ, Fulginiti V, Walterfang M. Inborn errors of metabolism associated with psychosis: literature review and case-control study using exome data from 5090 adult individuals. J Inherit Metab Dis. 2018;41(4):613–621.
  119. Crow YJ. Aicardi-Goutieres Syndrome. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993.
  120. Bernard G, Vanderver A. POLR3-related leukodystrophy. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993.
  121. Paloneva J, Autti T, Hakola P, et al. Polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993.
  122. de Boer I, Pelzer N, Terwindt G. Retinal vasculopathy with cerebral leukoencephalopathy and systemic manifestations. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993.
  123. Laugel V. Cockayne syndrome. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993.
  124. Dulski J, Sundal C, Wszolek Z. K. CSF1R–related disorder. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993.
  125. Min R, Abbink TEM, van der Knaap MS. Megalencephalic Leukoencephalopathy with Subcortical Cysts. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993.
  126. Waack A, Norris J, Becker K, et al. Leukoencephalopathy, calcifications, and cysts: Labrune syndrome. Radiol Case Rep. 2023;18(2):584–590.
  127. Sacharow SJ, Picker JD, Levy HL. Homocystinuria Caused by Cystathionine Beta-Synthase Deficiency. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993.
  128. Matsumoto S, Haberle J, Kido J, et al. Urea cycle disorders–update. J Hum Genet. 2019;64(9):833–847.
  129. Strauss KA, Puffenberger EG, Carson VJ. Maple syrup urine disease. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993.
  130. El-Hattab AW, Almannai M, Scaglia F. Melas. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993.
  131. Arnold G, Vockley J. Phenylalanine hydroxylase deficiency. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993.
  132. Weiss KH, Schilsky M. Wilson Disease. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993.
  133. Patterson M. Niemann-Pick Disease Type C. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993.
  134. de Los Reyes E, Lehwald L, Augustine EF, et al. Intracerebroventricular cerliponase alfa for neuronal ceroid lipofuscinosis type 2 disease: clinical practice considerations from US clinics. Pediatr Neurol. 2020;110:64–70.
  135. Ficicioglu C, Stepien KM. Alpha-mannosidosis. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993.
  136. Tokatly Latzer I, Pearl PL, Roullet JB. Succinic semialdehyde dehydrogenase deficiency. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews((R)). Seattle (WA)1993. 

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