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Table of Contents    
Year : 2021  |  Volume : 69  |  Issue : 6  |  Page : 1838-1840

A Rare Cause of Globus Pallidus and Dentate Nucleus Hyperintensity in Childhood: MBOAT Mutation

Division of Child Neurology, Faculty of Medicine, Istanbul Medipol University, Istanbul, Turkey

Date of Submission22-Mar-2021
Date of Decision22-Nov-2021
Date of Acceptance30-Nov-2021
Date of Web Publication23-Dec-2021

Correspondence Address:
Dr. Esra Ozpinar
Division of Child Neurology, Faculty of Medicine, Istanbul Medipol University, Istanbul
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.333478

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 » Abstract 

Mutations in mammalian membrane-bound O-acyltransferase domain-containing (MBOAT) 7 gene are a rare cause for intellectual disability, developmental delay, autistic findings, epilepsy, truncal hypotonia with appendicular hypertonia, and below-average head sizes. Pathogenic variants in MBOAT7 gene show these nonspecific clinical features that are seen in many other neurometabolic diseases. Therefore, specific neuroimaging findings can be valuable key factors for differential diagnosis. Magnetic resonance imaging (MRI) findings of T2 hyperintensity in bilateral globus pallidi and dentate nuclei are seen in a few neurometabolic diseases with similar clinical features of developmental delay and hypotonia, as in our cases. While evaluating the patients with similar phenotypes and specific MRI findings, MBOAT7 deficiency should be kept in mind. Here, we identified two brothers who had a novel homozygous variant in MBOAT7 gene and aimed to raise awareness about this newly described disease.

Keywords: Dentate nucleus, globus pallidus, MBOAT7
Key Message: T2 hyperintensity in both bilateral globus pallidi and dentate nuclei are specific MRI findings that point to the diagnosis of rare neurometabolic diseases such as MBOAT7 deficiency.

How to cite this article:
Ozpinar E, Kaytan I, Topcu Y, Kılıc B, Aydin K. A Rare Cause of Globus Pallidus and Dentate Nucleus Hyperintensity in Childhood: MBOAT Mutation. Neurol India 2021;69:1838-40

How to cite this URL:
Ozpinar E, Kaytan I, Topcu Y, Kılıc B, Aydin K. A Rare Cause of Globus Pallidus and Dentate Nucleus Hyperintensity in Childhood: MBOAT Mutation. Neurol India [serial online] 2021 [cited 2022 Jan 18];69:1838-40. Available from:

Mammalian membrane-bound O-acyltransferase (MBOAT) protein family consists of five acyltransferases. The MBOAT7 gene is located on chromosome 19, encodes lysophosphatidylinositol acyltransferase-1 contributing to the regulation of free arachidonic acids in cells that take part in inflammation pathways.[1],[2],[3] MBOAT7 is involved in the development of cerebral cortex in mammals.[1] Patients with MBOAT7 mutations have common brain magnetic resonance imaging (MRI) findings of cerebellar atrophy, disorganized cerebellar folia, and prominent perivascular spaces.[3] Patients showed a wide spectrum of clinical features, including intellectual disability (ID), epilepsy, autistic spectrum disorder (ASD), truncal hypotonia, and appendicular hypertonia that demonstrates the importance of inflammatory pathways in brain function.[1],[4],[5] Here, we present the clinical and genetic findings of two siblings with a novel pathogenic variant of MBOAT7 gene.

 » Case History Top

The two affected patients were brothers born to healthy consanguineous parents with no family history of neurologic diseases. The older brother was four years old who was referred to our clinic with global developmental delay in early milestones accompanied by truncal hypotonia, ID, and speech delay. He had no prenatal or postnatal insults and had normal birth weight and head circumference. Since birth he had shown a delay in neurodevelopmental milestones. He gained the ability to control his head at 8 months, sit independently at 1.5 years, walked independently at 2.5 years, and could speak only a few words. He had no seizures. Neurological examination showed truncal hypotonia and increased deep tendon reflexes. He had a below-average head size with 45.5 cm, which is 3–10 p. Routine laboratory tests and metabolic workup, including complete blood count, biochemistry, plasma amino acids, urinary organic acids, and carnitine–acylcarnitine profile, were normal. Electroencepahlogram was normal. Brain MRI showed T2 hyperintensity of bilateral symmetric globus pallidi and dentate nuclei [Figure 1] and [Figure 2].
Figure 1: Bilateral globus pallidi hyperintensity

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Figure 2: Bilateral dentate nuclei hyperintensity in T2

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The younger brother was 16 months old. He was full-term but followed up in neonatal intensive care unit for 10 days due to transient tachypnea of neonate. He could not gain head control. Neurological examination showed truncal hypotonia and increased deep tendon reflexes. His head circumference was 48.5 cm (10–25 p). He experienced myoclonic seizures since 12 months old. Vigabatrine treatment was begun. Routine laboratory tests and metabolic workup, including complete blood count, biochemistry, plasma amino acids, urinary organic acids and carnitine–acylcarnitine profile, were normal. Aspartate transaminase was 37.7 and alanine transaminase 23.2 U/L. The findings of brain MRI were similar to his brother's, including bilateral symmetric globus pallidi and dentate nuclei signal changes. We performed whole exome sequencing (WES) because the two brothers have similar symptoms, normal metabolic tests, and consanguineous parents. WES identified a homozygous, likely pathogenic variant in MBOAT7 gene (p. R271Pfs*25). Sanger sequencing method was used to confirm the mutation. Segregation analysis revealed that the unaffected parents were both heterozygous for the same variant.

 » Discussion Top

We describe two brothers with a novel, homozygous, likely pathogenic variant in the MBOAT7 (p.R271Pfs*25), who had global developmental and speech delay with basal ganglia hyperintensities. The p.R271Pfs*25 variant is not present in Exome Aggregation Consortium, ClinVar, 1,000 Genomes Project, or Genome Aggregation Database.

Farnè et al.[3] described 44 published cases of neurological disorder related to MBOAT7 mutations in 2020. Forty-two cases are born from consanguineous parents. All cases had ID. The other common symptoms are delayed motor milestones (41/44) with speech (41/44) and motor delay (37/40), seizures (32/40; myoclonic: 8/37), and truncal hypotonia (35/37).[3] Delayed early milestones and hypotonia were two presenting symptoms in our patients. ID and severe speech delay were other findings. Epilepsy was present in the younger brother with myoclonic seizures. Unlike the patients reported by Johansen et al.,[6] our patients had no hypertonia. Hypotonia was noted in our patients along with delayed early motor milestones. Microcephalic, macrocephalic, and normocephalic patients are notified in reviews. Our patients had head circumferences within the normal range.

Brain MRI findings, such as cortical atrophy, polymicrogyria, leukoencephalopathy, and cerebellar dysgenesis (22/40) had been described by Farnè et al.[3]. Johansen et al.[6] reported normal MRI findings except in two subjects who had cortical atrophy and mild polymicrogyria. Heidaria et al.[1] also described three patients with the presence of globus pallidus signal changes in MRI. Our patients had T2 hyperintensity in both dentate nuclei and globus pallidi in MRI, which could support the diagnosis of the disease. Other diseases that cause the same MRI findings include methylmalonic acidemia, succinic semialdehyde dehydrogenase deficiency, pyruvate dehydrogenase deficiency, l-2-hydroxyglutaric aciduria, and glutaric aciduria type 1. Because most of the patients with these diseases present with developmental delay and hypotonia, as in our cases, differential diagnosis is often difficult to make. Long examination and investigation processes are mostly required for a definite diagnosis. Clinical information and different presentations of these rare diseases should be well-known to reach a definite diagnosis in a short period.

MBOAT7 protein has a role in liver homeostasis, and some genetic variants increase the risk of fatty and alcoholic liver cirrhosis with elevated phosphatidylinositol turnover. A common variation, MBOAT7 rs641738, was also shown to be associated with cancer and fatty and alcoholic liver disease. Mice with specific downregulation of the MBOAT7 in the liver showed normal cognitive function and higher fat in the liver. Therefore, chronic liver changes can be a clue for this disease. Chronic liver diseases also involve in differential diagnosis of signal changes of globus pallidi and dentate nuclei. Nevertheless, we did not trace any sign of fatty liver diseases in our patients by checking liver enzymes, but the presence of globus pallidus signal changes in MRI might be indicative of metabolic changes as a result of loss of MBOAT7 expression in hepatic cells. It should be kept in mind that liver functions may not be affected in the early period; some patients had high liver enzyme levels after diagnosis. Due to the young age of our patients, the liver disease might manifest later, so should be screened periodically.[7],[8]

In conclusion, we report a novel genetic variant in MBOAT7 gene causing ID and hypotonia in the two brothers. Although the same mutation was detected, one patient had epilepsy and the other patient did not. We suggest that the MBOAT7 gene defects in the differential diagnosis of neurometabolic diseases might cause hyperintensity in globus pallidi and dentate nuclei with ID, seizure, developmental delay, especially with no sudden exaggeration in existing symptoms or progressive course. Because this disease was described in recent years, MBOAT7 deficiency should be kept in mind. WES is important in the identification of rare and novel neurometabolic diseases, defining different phenotypes and MRI findings providing recognition of diseases with the same genetics. We want to notify differential diagnosis of specific MRI findings with MBOAT7 disease that are not defined in detail.

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Conflicts of interest

There are no conflicts of interest.

 » References Top

Heidaria E, Caddeo A, Zarabadi K, Masoudi M, Tavasoli AR, Romeo S, et al. Identification of novel loss of function variants in MBOAT7 resulting in intellectual disability. Genomics 2020;112:4072-7.  Back to cited text no. 1
Khan S, Rawlins LE, Harlalka GV, Umair M, Ullah A, Shahzad S, et al. Homozygous variants in the HEXB and MBOAT7 genes underlie neurological diseases in consanguineous families. BMC Med Genet 2019;20:199.  Back to cited text no. 2
Farnè M, Tedesco GM, Bedetti C, Mencarelli A, Rogaia D, Colavito D, et al. A patient with novel MBOAT7 variant: The cerebellar atrophy is progressive and displays a peculiar neurometabolic profile. Am J Med Genet A 2020;182:2377-83.  Back to cited text no. 3
Jacher JE, Roy N, Ghaziuddin M, Innis JW. Expanding the phenotypic spectrum of MBOAT7-related intellectual disability. Am J Med Genet 2019;180B:483-7.  Back to cited text no. 4
Yalnızoglu D, Ozgul RK, Oguz KK, Ozer B, Yücel-Yılmaz D, Gürbüz B, et al. Expanding the phenotype of phospholipid remodelling disease due to MBOAT7 gene defect. J Inherit Metab Dis 2019;42:381-8.  Back to cited text no. 5
Johansen A, Rosti RO, Musaev D, Sticca E, Harripaul R, Zaki M, et al. Mutations in MBOAT7, encoding lysophosphatidylinositol acyltransferase I, lead to intellectual disability accompanied by epilepsy and autistic features. Am J Hum Genet 2016;99:912-6.  Back to cited text no. 6
Thangapandi VR, Knittelfelder O, Brosch M, Patsenker E, Vvedenskaya O, Buch S, et al. Loss of hepatic Mboat7 leads to liver fibrosis. Gut 2021;70:940-50.  Back to cited text no. 7
Mancina RM, Dongiovanni P, Petta S, Pingitore P, Meroni M, Rametta R, et al. The MBOAT7-TMC4 variant rs641738 increases risk of nonalcoholic fatty liver disease in individuals of European descent. Gastroenterology 2016;150:1219-30.  Back to cited text no. 8


  [Figure 1], [Figure 2]


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