1
|
Mishra N, Pathak KK, Prasad S, Mishra D. Acute encephalopathy in a neonate: a diagnostic odyssey leading to maple syrup urine disease (MSUD). BMJ Case Rep 2025; 18:e263603. [PMID: 40132917 DOI: 10.1136/bcr-2024-263603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/27/2025] Open
Abstract
We report a rare case of a term neonate presented with seizure, encephalopathy and respiratory distress, with an initial sepsis screen, serum electrolytes, blood sugar and cerebrospinal fluid (CSF) examination revealing no abnormalities. However, CT scan and MRI showed diffuse brain white matter oedema, and tandem mass spectroscopy and gas chromatography revealed elevated levels of branched chain amino acids and their ketoacids and hydroxy acids in urine. Clinical exome sequencing confirmed a mutation in the BCKDHB gene, diagnosing classical variety of maple syrup urine disease (MSUD). The baby was managed with high glucose infusion and a specialised branched-chain amino acid-free formula. This case highlights the importance of considering inborn error of metabolism (IEM) in neonates with encephalopathy and negative sepsis screens, using advanced imaging and metabolomics for timely and accurate diagnosis, prompt management to prevent ongoing encephalopathy and optimise long-term neurodevelopmental outcome. Early recognition and intervention in IEM cases can significantly impact patient outcomes, highlighting the need for a multidisciplinary approach to diagnosis and treatment.
Collapse
Affiliation(s)
- Neeraj Mishra
- Neonatology, Twinke Toes Paediatric Superspeciality Hospital, Patna, Bihar, India
| | - Keshav Kumar Pathak
- Neonatology, All India Institute of Medical Sciences Patna, Patna, Bihar, India
| | - Santosh Prasad
- Radiology, Patna Medical College and Hospital, Patna, Bihar, India
| | - Divya Mishra
- Paediatrics and Neonatology, Twinkle Toes Paediatric Superspeciality Hospital, Patna, Bihar, India
| |
Collapse
|
2
|
Lavery S, Adepoju TE, Fisher HB, Chan C, Kuhs A, Ahrens-Nicklas RC, White BR. Functional connectivity changes in mouse models of maple syrup urine disease. Cereb Cortex 2025; 35:bhaf040. [PMID: 40037414 PMCID: PMC11879283 DOI: 10.1093/cercor/bhaf040] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 01/13/2025] [Accepted: 02/01/2025] [Indexed: 03/06/2025] Open
Abstract
Maple syrup urine disease is a rare metabolic disorder that results in neurodevelopmental injury despite dietary therapy. While structural neuroimaging has shown a characteristic pattern of edema and white matter injury, no functional neuroimaging studies of maple syrup urine disease have been performed. Using widefield optical imaging, we investigated resting-state functional connectivity in two brain-specific mouse models of maple syrup urine disease (an astrocyte-specific knockout and a whole-brain knockout). At 8 weeks, mouse functional neuroimaging was performed using a custom-built widefield optical imaging system. Imaging was performed before and after initiation of a high-protein diet for 1 week to mimic metabolic crisis, which we hypothesized would result in decreased functional connectivity strength. Data were analyzed using seed-based functional connectivity and cluster-based inference. Astrocyte-specific knockout mice developed increased contralateral functional connectivity within the posteromedial somatosensory cortex after diet initiation. Whole-brain knockout mice had a similar pattern present at baseline, which persisted after diet initiation. Thus, contrary to expectations, maple syrup urine disease resulted in increased functional connectivity strength, especially after diet initiation. While the underlying etiology of these changes is unclear, these results demonstrate that inborn errors of metabolism result in changes to functional connectivity networks. Further research may demonstrate functional neuroimaging biomarkers that could be translated to clinical care.
Collapse
Affiliation(s)
- Sarah Lavery
- Division of Cardiology, Department of Pediatrics, The Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, 3401 Civic Center Blvd., Pediatric Cardiology – 8NW, Philadelphia, PA 19104, United States
| | - Temilola E Adepoju
- Division of Cardiology, Department of Pediatrics, The Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, 3401 Civic Center Blvd., Pediatric Cardiology – 8NW, Philadelphia, PA 19104, United States
| | - Hayden B Fisher
- Division of Cardiology, Department of Pediatrics, The Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, 3401 Civic Center Blvd., Pediatric Cardiology – 8NW, Philadelphia, PA 19104, United States
| | - Claudia Chan
- Division of Cardiology, Department of Pediatrics, The Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, 3401 Civic Center Blvd., Pediatric Cardiology – 8NW, Philadelphia, PA 19104, United States
| | - Amanda Kuhs
- Division of Human Genetics, Department of Pediatrics, The Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, 3615 Civic Center Blvd., Philadelphia, PA 19104, United States
| | - Rebecca C Ahrens-Nicklas
- Division of Human Genetics, Department of Pediatrics, The Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, 3615 Civic Center Blvd., Philadelphia, PA 19104, United States
| | - Brian R White
- Division of Cardiology, Department of Pediatrics, The Children’s Hospital of Philadelphia and the Perelman School of Medicine at the University of Pennsylvania, 3401 Civic Center Blvd., Pediatric Cardiology – 8NW, Philadelphia, PA 19104, United States
| |
Collapse
|
3
|
Salari M, Etemadifar M, Ashourizadeh H. Diffuse subcortical white matter restriction: An uncommon finding on metronidazole toxicity. Neuroradiol J 2023; 36:119-124. [PMID: 35850612 PMCID: PMC9893164 DOI: 10.1177/19714009221111087] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Metronidazole is a common and widely used antibiotic to treat a wide range of infectious diseases and has been associated with serious neurologic disturbances which in some cases were irreversible. We present a metronidazole-induced encephalopathy in a 19-year-old girl after 7 days of metronidazole treatment, with diffusion restricted subcortical white matter lesions along with the corpus callosum involvements. Diverse clinical presentation of a serious neurologic disturbance caused by a common widely used antibiotic should be carefully addressed in the setting of both short- and long-term treatment.
Collapse
Affiliation(s)
- Mehri Salari
- Functional Neurosurgery Research
Center, Shohada Tajrish Neurosurgical Center of Excellence, Shahid Beheshti University of Medical
Sciences, Tehran, Iran
| | - Masoud Etemadifar
- Department of Functional
Neurosurgery, Medical School, Isfahan University of Medical
Science, Isfahan, Iran
| | - Helia Ashourizadeh
- Functional Neurosurgery Research
Center, Shohada Tajrish Neurosurgical Center of Excellence, Shahid Beheshti University of Medical
Sciences, Tehran, Iran
| |
Collapse
|
4
|
Liu Q, Li F, Zhou J, Liu X, Peng J, Gong L. Neonatal maple syrup urine disease case report and literature review. Medicine (Baltimore) 2022; 101:e32174. [PMID: 36550798 PMCID: PMC9771221 DOI: 10.1097/md.0000000000032174] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
RATIONALE The main clinical symptoms of maple syrup urine disease (MSUD) are dehydration, acidosis, nervous system symptoms and intellectual disability. The brain imaging findings were mainly caused by cytotoxic edema. The lesions usually occur at the site consistent with the myelination process of normal neonates. The distribution is mostly symmetric, and the diffusion is obviously limited. PATIENT CONCERNS Herein, we report a rare case of an 8-day-old female patient who presented with abnormal symptoms, such as difficulty eating, convulsions, slow reaction, difficulty in correcting hypoglycemia and severe metabolic disorders. Brain magnetic resonance imaging (MRI) revealed abnormal signal intensity mainly involving the brainstem, cervical spinal cord, bilateral cerebellar hemispheres, basal ganglia, thalamus, precentral gyrus, and postcentral gyrus with characteristic hyperintensity on diffusion-weighted imaging (DWI) sequence. MSUD is rarely reported, while cervical spinal cord involvement is extremely rare. DIAGNOSES Blood tandem mass spectrometry, urine organic acid detection, and genetic disease overall genetic tests were performed to further confirm the diagnosis of MSUD. INTERVENTIONS Under general anesthesia, she underwent open surgical procedures for liver transplantation. OUTCOMES The child was in a stable condition after liver transplantation, and the diet was not restricted. LESSONS MSUD in neonates is rare. Our case report and literature review was aim to describe the clinic and imaging characteristics of it, and highlight physicians must be aware of this entity in newborns so as to reduce misdiagnosis due to unfamiliarity.
Collapse
Affiliation(s)
- Qiao Liu
- Department of Medical Imaging Center, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Fang Li
- Department of Medical Imaging Center, Ganzhou People’s Hospital, Ganzhou, China
| | - Jingjing Zhou
- Department of Medical Imaging Center, Second Affiliated Hospital of Nanchang University, Nanchang, China
| | - Xiaoyu Liu
- Department of Medical Imaging Center, Ganzhou People’s Hospital, Ganzhou, China
| | - Jidong Peng
- Department of Medical Imaging Center, Ganzhou People’s Hospital, Ganzhou, China
| | - Lianggeng Gong
- Department of Medical Imaging Center, Second Affiliated Hospital of Nanchang University, Nanchang, China
- * Correspondence: Lianggeng Gong, Department of Medical Imaging Center, Second Affiliated Hospital of Nanchang University, Nanchang, China (e-mail: )
| |
Collapse
|
5
|
Mohamed MM, Bakheet MA, Magdy RM, El-Abd HS, Alam-Eldeen MH, Abo-Haded HM. The clinico-radiological findings of MSUD in a group of Egyptian children: Contribution to early diagnosis and outcome. Mol Genet Genomic Med 2021; 9:e1790. [PMID: 34432377 PMCID: PMC8580081 DOI: 10.1002/mgg3.1790] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2021] [Revised: 08/15/2021] [Accepted: 08/16/2021] [Indexed: 12/26/2022] Open
Abstract
Background Maple syrup urine disease (MSUD) is an autosomal recessive inborn error of amino acid metabolism, with unique clinico‐radiological findings. This study aims to show the benefit of using the clinico‐radiological findings for early diagnosis of children with MSUD, and confirming this diagnosis using the tandem mass spectrometry (MS/MS), in order to avoid deleterious outcome. Methods A prospective cohort study conducted in the period from August 2016 to December 2020. Twenty‐one children were included either by selective screening or by high‐risk screening. All children had clinical and neurodevelopmental evaluation, brain magnetic resonance imaging (MRI) assessment, and blood amino acids analysis at diagnosis. Patients were followed clinically. Results Most children had acute onsets neuro‐developmental symptoms, with wide range of brain parenchyma involvement on MRI (hyperintensity). Diagnosis of MSUD was confirmed by detecting high serum levels of leucine/isoleucine (mean value 2085.5 μmol/L) in all patients, and elevated levels of serum valine in (81%) of children. In addition, all children showed elevated leucine: alanine ratio, and leucine: phenylalanine ratio. Conclusions The characteristic clinico‐radiological features can help in the early diagnosis of MSUD children, thus preventing the delay in laboratory diagnosis and improving their outcomes.
Collapse
Affiliation(s)
- Montaser M Mohamed
- Pediatric Neurology Unit, Department of Pediatrics, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Mohamed A Bakheet
- Pediatric Cardiology Unit, Department of Pediatrics, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Rofaida M Magdy
- Metabolic and Genetic Unit, Department of Pediatrics, Faculty of Medicine, Sohag University, Sohag, Egypt
| | - Heba S El-Abd
- Department of Medical Genetics, Faculty of Medicine, Ain Shams University, Cairo, Egypt
| | | | - Hany M Abo-Haded
- Pediatric Cardiology Unit, Department of Pediatrics, Faculty of Medicine, Mansoura University, Mansoura, Egypt
| |
Collapse
|
6
|
Chavan R, Kadam S, Bhalke A, Choudhary SL, Patil P. Evaluation of Neonatal Acute Metabolic Crisis in Maple Syrup Urine Disease with MR Diffusion and MR Spectroscopy: Case Series and Review of the Literature. JOURNAL OF PEDIATRIC NEUROLOGY 2021. [DOI: 10.1055/s-0041-1726312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
Abstract
AbstractMagnetic resonance imaging (MRI) findings of acute metabolic crisis in maple syrup urine disease (MSUD) in neonates were reviewed. This case cohort study included six MSUD neonates imaged during acute metabolic decompensation. Specific diffusion imaging and proton spectroscopic findings were reviewed. All patients revealed extensive intramyelinic cytotoxic edema typically involving myelinated white matter structures. Brainstem, cerebellar white matter and peduncles, midbrain, posterior limbs of internal capsules, central portions of periventricular, and perirolandic white matter regions showed typical MSUD edema. Gray matter structures such as dentate nucleus and thalamus were involved in all patients. Involvement of other deep nuclei was also noted in a few patients. None of the patients showed involvement of the superficial cortex. Reduction in N-acetyl aspartate, a prominent lactate peak, and a peak representing methyl groups of amino acids were characteristic findings seen on intermediate short echo time MR spectroscopy. Our case series outlines the importance of diffusion and spectroscopy MR techniques in the diagnosis of acute neonatal MSUD metabolic crisis.
Collapse
Affiliation(s)
- Rajendra Chavan
- Anushka MRI & CT Scan Centre, King Edward Memorial Hospital, Pune, Maharashtra, India
| | - Sandeep Kadam
- Department of Pediatrics, King Edward Memorial Hospital, Pune, Maharashtra, India
| | - Amit Bhalke
- Department of Radiodiagnosis, King Edward Memorial Hospital, Pune, Maharashtra, India
| | - Sohan Lal Choudhary
- Department of Radiodiagnosis, King Edward Memorial Hospital, Pune, Maharashtra, India
| | - Pushpak Patil
- Department of Radiodiagnosis, King Edward Memorial Hospital, Pune, Maharashtra, India
| |
Collapse
|
7
|
Li Y, Liu X, Duan CF, Song XF, Zhuang XH. Brain magnetic resonance imaging findings and radiologic review of maple syrup urine disease: Report of three cases. World J Clin Cases 2021; 9:1844-1852. [PMID: 33748233 PMCID: PMC7953394 DOI: 10.12998/wjcc.v9.i8.1844] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/18/2020] [Revised: 12/12/2020] [Accepted: 01/21/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Maple syrup urine disease (MSUD) is a rare autosomal-recessive disorder that affects branched-chain amino acid (BCAA) metabolism and is named after the distinctive sweet odor of affected infants’ urine. This disease is characterized by the accumulation of BCAAs and corresponding branched-chain ketoacids of leucine, isoleucine, and valine in the plasma, urine, and cerebrospinal fluid. However, the mechanisms of MSUD-induced brain damage remain poorly defined. The accumulation of BCAAs in the brain inhibits the activity of pyruvate dehydrogenase and α-ketoglutarate, disrupting the citric acid cycle and consequently impacting the synthesis of amino acids, causing cerebral edema and abnormal myelination.
CASE SUMMARY We report three neonates admitted to our hospital with the classic subtype of MSUD. All three patients, with a transient normal period, presented with poor feeding, vomiting, poor weight gain, and increasing lethargy after birth. Laboratory testing revealed metabolic acidosis. The serum tandem mass spectrometry amino acid profile showed elevated plasma levels of BCAAs (leucine, isoleucine, and valine). Brain magnetic resonance imaging (MRI) presented abnormal signals mainly involving the globus pallidus, thalamus, internal capsule, brainstem, and cerebellar white matter, which represent the typical myelinated areas in normal full-term neonates.
CONCLUSION In our patients, MRI showed typical features, in concordance with the available literature. Early detection and timely treatment are very helpful for the prognosis of MSUD patients. Therefore, we discuss the neuroimaging features of MSUD to enhance the knowledge of pediatricians about this disease.
Collapse
Affiliation(s)
- Yang Li
- Department of Radiology, Qingdao Women and Children’s Hospital, Qingdao 266011, Shandong Province, China
| | - Xia Liu
- Department of Ultrasound, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Chong-Feng Duan
- Department of Radiology, The Affiliated Hospital of Qingdao University, Qingdao 266000, Shandong Province, China
| | - Xiu-Feng Song
- Department of Radiology, Qingdao Women and Children’s Hospital, Qingdao 266011, Shandong Province, China
| | - Xun-Hui Zhuang
- Department of Radiology, Qingdao Women and Children’s Hospital, Qingdao 266011, Shandong Province, China
| |
Collapse
|
8
|
Brain Branched-Chain Amino Acids in Maple Syrup Urine Disease: Implications for Neurological Disorders. Int J Mol Sci 2020; 21:ijms21207490. [PMID: 33050626 PMCID: PMC7590055 DOI: 10.3390/ijms21207490] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Revised: 10/02/2020] [Accepted: 10/09/2020] [Indexed: 12/16/2022] Open
Abstract
Maple syrup urine disease (MSUD) is an autosomal recessive disorder caused by decreased activity of the branched-chain α-ketoacid dehydrogenase complex (BCKDC), which catalyzes the irreversible catabolism of branched-chain amino acids (BCAAs). Current management of this BCAA dyshomeostasis consists of dietary restriction of BCAAs and liver transplantation, which aims to partially restore functional BCKDC activity in the periphery. These treatments improve the circulating levels of BCAAs and significantly increase survival rates in MSUD patients. However, significant cognitive and psychiatric morbidities remain. Specifically, patients are at a higher lifetime risk for cognitive impairments, mood and anxiety disorders (depression, anxiety, and panic disorder), and attention deficit disorder. Recent literature suggests that the neurological sequelae may be due to the brain-specific roles of BCAAs. This review will focus on the derangements of BCAAs observed in the brain of MSUD patients and will explore the potential mechanisms driving neurologic dysfunction. Finally, we will discuss recent evidence that implicates the relevance of BCAA metabolism in other neurological disorders. An understanding of the role of BCAAs in the central nervous system may facilitate future identification of novel therapeutic approaches in MSUD and a broad range of neurological disorders.
Collapse
|
9
|
Liu YD, Chu X, Liu RH, Sun Y, Kong QX, Li QB. Paroxysmal spasticity of lower extremities as the initial symptom in two siblings with maple syrup urine disease. Mol Med Rep 2019; 19:4872-4880. [PMID: 30957186 PMCID: PMC6522870 DOI: 10.3892/mmr.2019.10133] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2018] [Accepted: 04/01/2019] [Indexed: 12/28/2022] Open
Abstract
Maple syrup urine disease (MSUD) is a rare autosomal recessive metabolic disorder caused by mutations in genes that encode subunits of the branched‑chain α‑ketoacid dehydrogenase (BCKD) complex. Impairment of the BCKD complex results in an abnormal accumulation of branched‑chain amino acids and their corresponding branched‑chain keto acids in the blood and cerebrospinal fluid, which are neurovirulent and may become life‑threatening. An 11‑day‑old boy was admitted to the hospital with paroxysmal spasticity of lower extremities. Of note, his 10‑year‑old sister presented similar symptoms during the neonatal period, and her condition was diagnosed as MSUD when she was 1.5 years old. Genetic screening was performed, and the boy and his sister exhibited two novel compound heterozygous mutations in the branched chain keto acid dehydrogenase E1 subunit β (BCKDHB) gene: A substitution from guanine to adenine in the coding region at position 1,076 (c.1,076G>A) in exon 10 and a deletion of a thymine at position 705 (c.705delT) in exon 6. The missense mutation c.1076G>A results in an amino acid substitution from arginine to lysine at position 359 (p.Arg359Lys), whereas the mutation c.705delT results in the replacement of a cysteine at position 235 with a stop codon (p.Cys235Ter). Neither of the BCKDHB alleles in the compound heterozygote patients is able to generate normal E1β subunits, resulting in a possible impairment of the activity of the BCKD complex. In the present study, it was hypothesized that the two novel heterozygous mutations in the BCKDHB gene found in the Chinese family may be responsible for the phenotype of the two siblings with MSUD.
Collapse
Affiliation(s)
- Yi-Dan Liu
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Xu Chu
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Rui-Hua Liu
- Department of Pediatrics, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Ying Sun
- Cheeloo College of Medicine, Shandong University, Jinan, Shandong 250012, P.R. China
| | - Qing-Xia Kong
- Department of Neurology, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, P.R. China
| | - Qiu-Bo Li
- Department of Pediatrics, Affiliated Hospital of Jining Medical University, Jining, Shandong 272000, P.R. China
| |
Collapse
|
10
|
Cheng A, Han L, Feng Y, Li H, Yao R, Wang D, Jin B. MRI and clinical features of maple syrup urine disease: preliminary results in 10 cases. Diagn Interv Radiol 2018; 23:398-402. [PMID: 28830848 DOI: 10.5152/dir.2017.16466] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
PURPOSE We aimed to evaluate the magnetic resonance imaging (MRI) and clinical features of maple syrup urine disease (MSUD). METHODS This retrospective study consisted of 10 MSUD patients confirmed by genetic testing. All patients underwent brain MRI. Phenotype, genotype, and areas of brain injury on MRI were retrospectively reviewed. RESULTS Six patients (60%) had the classic form of MSUD with BCKDHB mutation, three patients (30%) had the intermittent form (two with BCKDHA mutations and one with DBT mutation), and one patient (10%) had the thiamine-responsive form with DBT mutation. On diffusion-weighted imaging, nine cases presented restricted diffusion in myelinated areas, and one intermittent case with DBT mutation was normal. The classic form of MSUD involved the basal ganglia in six cases; the cerebellum, mesencephalon, pons, and supratentorial area in five cases; and the thalamus in four cases, respectively. The intermittent form involved the cerebellum, pons, and supratentorial area in two cases. The thiamine-responsive form involved the basal ganglia and supratentorial area. CONCLUSION Our preliminary results indicate that patients with MSUD presented more commonly in classic form with BCKDHB mutation and displayed extensive brain injury on MRI.
Collapse
Affiliation(s)
- Ailan Cheng
- Department of Radiology, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | | | | | | | | | | | | |
Collapse
|
11
|
Kakkar C, Kakkar S, Saggar K, Goraya JS, Ahluwalia A, Arora A. Paediatric brainstem: A comprehensive review of pathologies on MR imaging. Insights Imaging 2016; 7:505-22. [PMID: 27216793 PMCID: PMC4956624 DOI: 10.1007/s13244-016-0496-3] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2015] [Revised: 03/13/2016] [Accepted: 04/22/2016] [Indexed: 01/29/2023] Open
Abstract
The brainstem is a midline structure formed by the midbrain, pons and medulla and is a home for various vital neurological centres of the human body. A diverse spectrum of disease entities can involve the brainstem, which includes infections, metabolic disorders, demyelination, vascular conditions, neurodegenerative disorders and tumours. Brainstem involvement can be primary or secondary, i.e., as part of systemic disorders. Due to the overlapping clinical presentation and symptomatology, imaging plays a decisive role in the detection, localisation and characterisation of brainstem pathologies. Magnetic resonance imaging (MRI) is the modality of choice and the use of advanced MR techniques such as diffusion-weighted imaging and spectroscopy can be especially helpful in providing a tenable diagnoses. This article is a compilation of the MR imaging manifestations of a spectrum of common and uncommon brainstem pathologies that can be encountered in the paediatric age group. Teaching Points • The paediatric brainstem can be afflicted by many pathologies that may overlap clinico-radiologically. • MRI is the best modality for the localisation and diagnosis of brainstem pathologies. • Diffusion-weighted imaging is useful in the diagnosis of vascular and metabolic disorders. • Occasionally, demyelination and neoplasms can be indistinguishable on imaging.
Collapse
Affiliation(s)
- Chandan Kakkar
- Department of Radiodiagnosis and Imaging, Dayanand Medical College and Hospital, Ludhiana, India.
| | - Shruti Kakkar
- Division of Pediatric Haemato-oncology, Department of Pediatrics, Dayanand Medical College and Hospital, Ludhiana, India
| | - Kavita Saggar
- Department of Radiodiagnosis and Imaging, Dayanand Medical College and Hospital, Ludhiana, India
| | - Jatinder S Goraya
- Division of Pediatric Neurology, Department of Pediatrics, Dayanand Medical College and Hospital, Ludhiana, India
| | - Archana Ahluwalia
- Department of Radiodiagnosis and Imaging, Dayanand Medical College and Hospital, Ludhiana, India
| | - Ankur Arora
- Worthing Hospital, Western Sussex NHS Foundation Trust, Lyndhurst Road, Worthing, BN112DH, UK
| |
Collapse
|
12
|
Dahmoush HM, Melhem ER, Vossough A. Metabolic, endocrine, and other genetic disorders. HANDBOOK OF CLINICAL NEUROLOGY 2016; 136:1221-1259. [PMID: 27430466 DOI: 10.1016/b978-0-444-53486-6.00063-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/06/2023]
Abstract
Metabolic, endocrine, and genetic diseases of the brain include a very large array of disorders caused by a wide range of underlying abnormalities and involving a variety of brain structures. Often these disorders manifest as recognizable, though sometimes overlapping, patterns on neuroimaging studies that may enable a diagnosis based on imaging or may alternatively provide enough clues to direct further diagnostic evaluation. The diagnostic workup can include various biochemical laboratory or genetic studies. In this chapter, after a brief review of normal white-matter development, we will describe a variety of leukodystrophies resulting from metabolic disorders involving the brain, including mitochondrial and respiratory chain diseases. We will then describe various acidurias, urea cycle disorders, disorders related to copper and iron metabolism, and disorders of ganglioside and mucopolysaccharide metabolism. Lastly, various other hypomyelinating and dysmyelinating leukodystrophies, including vanishing white-matter disease, megalencephalic leukoencephalopathy with subcortical cysts, and oculocerebrorenal syndrome will be presented. In the following section on endocrine disorders, we will examine various disorders of the hypothalamic-pituitary axis, including developmental, inflammatory, and neoplastic diseases. Neonatal hypoglycemia will also be briefly reviewed. In the final section, we will review a few of the common genetic phakomatoses. Throughout the text, both imaging and brief clinical features of the various disorders will be discussed.
Collapse
Affiliation(s)
- Hisham M Dahmoush
- Department of Radiology, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, USA
| | - Elias R Melhem
- Department of Diagnostic Radiology and Nuclear Medicine, University of Maryland, Baltimore, MD, USA
| | - Arastoo Vossough
- Department of Radiology, Children's Hospital of Philadelphia and University of Pennsylvania, Philadelphia, PA, USA.
| |
Collapse
|
13
|
Guo Y, Liming L, Jiang L. Two novel compound heterozygous mutations in the BCKDHB gene that cause the intermittent form of maple syrup urine disease. Metab Brain Dis 2015; 30:1395-400. [PMID: 26239723 DOI: 10.1007/s11011-015-9711-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2015] [Accepted: 07/15/2015] [Indexed: 10/23/2022]
Abstract
Intermittent maple syrup urine disease (MSUD) is a potentially life-threatening metabolic disorder caused by a deficiency of branched chain α-ketoacid dehydrogenase (BCKD) complex. In contrast to classic MSUD, children with the intermittent form usually have an atypical clinical manifestation. Here, we describe the presenting symptoms and clinical course of a Chinese boy with intermittent MSUD. Mutation analysis identified two previously unreported mutations in exon 7 of the BCKDHB gene: c.767A > G (p.Y256C) and c.768C > G (p.Y256X); the parents were each heterozygous for one of these mutations. In silico analysis predicted Y256C probably affects protein structure; Y256X leads to a premature stop codon. This case demonstrates intermittent MSUD should be suspected in cases with symptoms of recurrent encephalopathy, especially ataxia or marked drowsiness, which usually present after the neonatal period and in conjunction with infection. symmetrical basal ganglia damage but normal myelination in the posterior limb will assist differential diagnosis; alloisoleucine is a useful diagnostic marker and mutation analysis may be of prognostic value. These novel mutations Y256C and Y256X result in the clinical manifestation of a variant form of MSUD, expanding the mutation spectrum of this disease.
Collapse
Affiliation(s)
- Yi Guo
- Department of Neurology, Children's Hospital of Chongqing Medical University, Chongqing, China, 400014.
| | - Liu Liming
- Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China.
| | - Li Jiang
- Department of Neurology, Children's Hospital of Chongqing Medical University, Chongqing, China, 400014.
- Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China.
| |
Collapse
|
14
|
Xia W, Yang W. Diffusion-weighted magnetic resonance imaging in a case of severe classic maple syrup urine disease. J Pediatr Endocrinol Metab 2015; 28:805-8. [PMID: 25879313 DOI: 10.1515/jpem-2014-0461] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/10/2014] [Accepted: 03/11/2015] [Indexed: 12/13/2022]
|
15
|
Jain A, Jagdeesh K, Mane R, Singla S. Imaging in classic form of maple syrup urine disease: a rare metabolic central nervous system. J Clin Neonatol 2013; 2:98-100. [PMID: 24049754 PMCID: PMC3775146 DOI: 10.4103/2249-4847.116411] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022] Open
Abstract
Maple syrup urine disease (MSUD) is a rare autosomal recessive disorder of branched-chain amino acid metabolism. The condition gets its name from the distinctive sweet odour of affected infants’ urine. MSUD is caused by a deficiency of the branched-chain α-ketoacid dehydrogenase enzyme complex, leading to accumulation of the branched-chain amino acids (leucine, isoleucine, and valine) and their toxic by-products (ketoacids) in the blood and urine. Imaging is characterestized by MSUD oedema affecting the myelinated white matter. We present a neonate with classic type of MSUD and its imaging features on computed tomography, conventional magnetic resonance imaging, diffusion-weighted imaging, and magnetic resonance spectroscopy.
Collapse
Affiliation(s)
- Aditi Jain
- Department of Radiodiagnosis, M S Ramaiah Medical College and Teaching Hospital, Bangalore, Karnataka, India
| | | | | | | |
Collapse
|
16
|
Rossi A, Ratelade J, Papadopoulos MC, Bennett JL, Verkman AS. Neuromyelitis optica IgG does not alter aquaporin-4 water permeability, plasma membrane M1/M23 isoform content, or supramolecular assembly. Glia 2012; 60:2027-39. [PMID: 22987455 DOI: 10.1002/glia.22417] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2012] [Accepted: 08/15/2012] [Indexed: 12/24/2022]
Abstract
Neuromyelitis optica (NMO) is thought to be caused by immunoglobulin G autoantibodies (NMO-IgG) against astrocyte water channel aquaporin-4 (AQP4). A recent study (Hinson et al. (2012) Proc Natl Acad Sci USA 109:1245-1250) reported that NMO-IgG inhibits AQP4 water permeability directly and causes rapid cellular internalization of the M1 but not M23 isoform of AQP4, resulting in AQP4 clustering, enhanced complement-dependent cytotoxicity, and tissue swelling. Here, we report evidence challenging this proposed mechanism of NMO-IgG-mediated pathology. We measured osmotic water permeability by stopped-flow light scattering on plasma membrane vesicles isolated from AQP4-expressing CHO cells, an approach that can detect changes in water permeability as small as 5% and is not confounded by internalization effects. We found similar single-molecule water permeability for M1-AQP4 tetramers and M23-AQP4 clusters (orthogonal arrays of particles, OAPs). Exposure of AQP4 to high concentrations of NMO-IgG from six seropositive NMO patients, and to high-affinity recombinant monoclonal NMO antibodies, did not reduce AQP4 water permeability. Also, NMO-IgG did not reduce water permeability in AQP4-reconstituted proteoliposomes. In transfected cells expressing M1- or M23-AQP4 individually, NMO-IgG caused more rapid internalization of M23- than M1-AQP4. In cells coexpressing both isoforms, M1- and M23-AQP4 comingled in OAPs that were internalized together in response to NMO-IgG. Super-resolution imaging and native gel electrophoresis showed that the size of AQP4 OAPs was not altered by NMO sera or recombinant NMO antibodies. We conclude that NMO-IgG does not: (i) inhibit AQP4 water permeability, (ii) cause preferential internalization of M1-AQP4, or (iii) cause intramembrane AQP4 clustering.
Collapse
Affiliation(s)
- Andrea Rossi
- Department of Medicine, University of California, San Francisco, California 94143, USA
| | | | | | | | | |
Collapse
|