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Table of Contents    
Year : 2020  |  Volume : 68  |  Issue : 3  |  Page : 669-672

Van der Knaap Disease (Vanishing White Matter) – Unusual Presentation in a Neonate: A Case Report

1 Associate Professor of Pediatrics, RAK Medical and Health Sciences University, Ras al Khaimah, United Arab Emirates; Former Assistant Professor of Pediatrics, Department of Pediatrics, Rangaraya Medical College, Kakinada, Andhra Pradesh, India
2 RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras al Khaimah, United Arab Emirates

Date of Web Publication6-Jul-2020

Correspondence Address:
Mr. Ammar Al Homsi
RAK College of Medical Sciences, RAK Medical and Health Sciences University, Ras al Khaimah
United Arab Emirates
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/0028-3886.289018

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 » Abstract 

Van der Knaap disease, also known as megalencephalic leukoencephalopathy with subcortical cysts (MLC), is a rare autosomal disorder, with no exact prevalence but more than 150 cases were reported in the literature. It was more prevalent in some ethnicities where consanguinity is common.[1] It is usually characterized by infantile-onset macrocephaly, cerebral leukoencephalopathy and mild neurological symptoms, and a slow course of functional deterioration.[2] Diagnosis is determined by suggestive clinical features and MRI findings that include leukodystrophy and subcortical cysts. Herein, we present a rare occurrence of Van der Knaap disease, in a 24-day-old female neonate with similar MRI findings, who presented with neonatal seizures for evaluation.

Keywords: Megalencephaly leukoencephalopathy, seizures, subcortical cysts, Van der Knaap disease
Key Messages: This case report outlines a rare occurrence of Van der Knaap disease in the neonatal period, and the patient does belong to the mentioned ethnic groups, which indicates that the disease may occur in other Indian communities.

How to cite this article:
Jhancy M, Al Homsi A, Chowdhury F, Hossain S, Ahamed R. Van der Knaap Disease (Vanishing White Matter) – Unusual Presentation in a Neonate: A Case Report. Neurol India 2020;68:669-72

How to cite this URL:
Jhancy M, Al Homsi A, Chowdhury F, Hossain S, Ahamed R. Van der Knaap Disease (Vanishing White Matter) – Unusual Presentation in a Neonate: A Case Report. Neurol India [serial online] 2020 [cited 2021 Jun 13];68:669-72. Available from:

Vanishing white matter, the description is given to a condition called megalencephalic leukoencephalopathy with subcortical cysts (MLC), or Van der Knaap disease. Individuals with this condition have a combination of the enlarged brain also called megalencephaly and abnormalities in the white matter of the brain also called leukoencephalopathy. The disease was documented in 1962, by Eickle, in a 36-year-old patient after her death in an autopsy; the patient had extensive neurological deterioration after minor physical trauma. An autopsy showed cystic areas in the cerebral white matter.[3]

Van der Knaap disease is a rare disease, and its prevalence was said to be less than 1 in 1,000,000. No effective systemic studies were conducted to determine the incidence around the world. Very few cases were reported in the neonatal period.

Patients with this disease suffer from neurodegenerative features which include mild gross motor developmental delay, gradual onset of ataxia, spasticity, dysarthria, dystonia, and sometimes extrapyramidal findings.

[4] Macrocephaly, a characteristic feature of this disease, typically present at birth or develops during the first year.[5] Epilepsy usually develops in all patients and during the early years of life. Seizures might be partial or generalized. They are generally controlled with medications and uncontrolled epilepsy is unusual. Mental retardation and cognitive regression are reported to be mild, though late progression may occur. These are the characteristic features of the classical phenotype. The other improving phenotype has a similar initial presentation followed by an improving clinical course, where motor function improves or normalizes.[4]

Many genes and proteins were studied, related to this disease. MLC1 gene mutation accounts for 75% of all cases, and the HEPACAM gene mutation was found in 20% of all cases.[4] The MLC1 gene, located on the long arm of chromosome 22qtel, encodes a plasma membrane protein found in the brain, spleen, and leukocytes.[4],[6] The HEPACAM gene, located on the long arm of chromosome 11 (11q24.2), encodes the protein GlialCAM. However, the role of these genes and their proteins in the impairment of brain function and development is unknown. About 5% of cases do not have an identified mutation. Inheritance can be autosomal recessive or autosomal dominant. This disease was more prevalent in the Agrawal community, from east India; however, it was also reported among Libyan Jews, the Turkish community, and Egyptians.[1] The reason for this distribution is unclear but it can be a result of higher consanguineous marriage.

MRI findings include:[7]

  • Megalencephaly
  • ”Swollen” appearance of the cerebral white matter defined by diffuse, bilateral, and symmetric T2-weighted hyperintensity and T1-weighted hypointensity of cerebral white matter
  • Bilateral subcortical cysts of CSF intensity affecting the anterior temporal regions and frontoparietal lobes which may increase in size due to further cerebral atrophy
  • Abnormal diffusion signal on diffusion-weighted magnetic resonance imaging (DWI), but mild in the cerebellar white matter
  • Sparing of the deep and cerebellar white matter.

Diagnosis is established with suggestive clinical features and MRI findings, if clinical features are inconclusive, molecular genetic testing can confirm the diagnosis.[4]

Management is by treatment of manifestations and prevention of complications, supportive therapy by physical therapy, speech therapy, special education, and antiepileptic drugs, and in case of increased risk of head trauma, wearing a helmet can be beneficial.

 » Case Report Top

A 24-day-old girl born out of a second-degree consanguineous marriage [Figure 1] in Hindu Indian family, presented to the emergency department with recurrent seizures.
Figure 1: Patient's macrocephaly with a prominent forehead

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She was born out of normal full-term delivery with normal weight and length, but head circumference (HC) was 36 cm. Her delivery was uneventful during the perinatal period. Except for icterus on day 3 of birth, the patient was normal till the 24th day of birth, and she was on exclusive breastfeeding and was gaining adequate weight. The patient was active and feeding well, with no feeding difficulties.

The patient had no siblings. No history of fever or head trauma. No significant family history.

On examination, the patient had myoclonic seizures in both upper and lower limbs. Her vitals were within the normal range. She had macrocephaly with HC of 39 cm [above the 97th percentile line for her age; [Figure 2]. Anterior fontanelle was normal, sutures were not separated, no dilated scalp veins, and both eyes were normal. There were no dimorphic features, and organomegaly was not found on abdominal palpation. The rest of the physical examination and neurological examinations were normal. Developmentally she appeared normal with good rooting, suckling reflexes, and she was recognizing her mother.
Figure 2: Child's head circumference lies above the 97th centile in the WHO growth chart 'Head circumference for age (Girls)'

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Routine blood examination reports were normal that revealed normal random blood sugar reading of 92 mg/dL and serum calcium was 8.7 mg/dL. Serum ammonia and capillary arterial blood gases were normal. Lumbar puncture for cerebrospinal fluid (CSF) analysis was done, and there was no evidence of meningitis. The electroencephalogram was normal, and the toxoplasmosis, rubella, cytomegalovirus, and herpes simplex virus (TORCH) profile turned positive for IgG rubella and HSV-1.

MRI brain [Figure 3] and [Figure 4] showed diffuse bilateral symmetrical white matter hyperintensities involving bilateral fronto-temporo-parieto-occipital areas, with irregular cystic areas in bilateral temporoparietal areas. Similar encephalopathic changes in MRI brain were seen not only in Van der Knaap disease but also in some inborn errors of metabolism such as urea cycle disorders, sulfite oxidase deficiency, and mitochondrial oxidative phosphorylation disorders.[8] However, this child was normal with no dysmorphic features, organomegaly, and acidosis except for the new-onset seizures, hence Van der Knaap disease was made as a diagnosis of exclusion.
Figure 3: Axial MRI brain. Showing extensive bilateral white matter change with subcortical cysts

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Figure 4: Axial and sagittal MRI brain. Showing irregular cystic areas in temporoparietal area

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The patient's seizures were controlled with phenobarbitone 5 mg/kg/day, and she was kept on the same drug for maintenance and was discharged after two days. Parents were counselled for poor prognosis, and the child was lost to follow-up after three months.

 » Discussion Top

Through this case, we report a rare occurrence of this disorder in neonates. As previously mentioned, this disease is commonly seen in certain communities or ethnic groups from North India, our patient does belong to one the ethnic group mentioned. Macrocephaly commonly presents in early infancy and is usually associated with developmental delay. Our patient had macrocephaly and seizures after birth. The MRI findings, macrocephaly, and associated seizures aided in the diagnosis of Van der Knaap disease. The MRI findings are the hallmark for the diagnosis of the disease. An infant with suggestive clinical features increased HC, and subcortical cysts on imaging should be suspected of Van der Knaap disease as one of the differentials, and further confirmatory tests are recommended, usually by genetic analysis.

The differential diagnosis of MLC includes metabolic disorders, Canavan's disease, and Alexander disease.[5] In our case, our limitation was the inability to do genetic testing because the patient was lost to follow-up.[9]

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.


We thank the parents of the patient described for allowing us to share their child's details.

Financial support and sponsorship

RAK Medical and Health University, Ras al Khaimah, United Arab Emirates will support us financially if needed.

Conflicts of interest

There are no conflicts of interest.

 » References Top

Roy U, Joshi B, Ganguly G. Van der Knaap disease: A rare disease with atypical features. BMJ Case Reports 2015 pii: bcr2015209831. doi: 10.1136/bcr-2015-209831.  Back to cited text no. 1
Sharma A, Gupta M, Gupta N, Garg A. Van der knaap disease: Megalencephalic leukoencephalopathy with subcortical cysts. Saudi J Med Med Sci 2016;4:238-9.  Back to cited text no. 2
[PUBMED]  [Full text]  
Van der Knaap M, Pronk J, Scheper G. Vanishing white matter disease. Lancet Neurol 2006;5:413-23.  Back to cited text no. 3
van der Knaap MS, Abbink TEM, Min R. Megalencephalic Leukoencephalopathy with Subcortical Cysts. 2003 Aug 11 [Updated 2018 Mar 29]. In: Adam MP, Ardinger HH, Pagon RA,et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2020.  Back to cited text no. 4
Van der Knaap M, Barth P, Stroink H, van Nieuwenhuizen O, Arts W, Hoogenraad F, Valk J. Leukoencephalopathy with swelling and a discrepantly mild clinical course in eight children. Ann Neurol 1995;37:324-34.  Back to cited text no. 5
Leegwater P, Yuan B, van der Steen J, Mulders J, Könst A, Boor P, et al. Mutations of MLC1 (KIAA0027), encoding a putative membrane protein, cause megalencephalic leukoencephalopathy with subcortical cysts. Am J Hum Genet 2001;68:831-8.  Back to cited text no. 6
Schiffmann R, van der Knaap M. Invited article: An MRI-based approach to the diagnosis of white matter disorders. Neurology 2009;72:750-9.  Back to cited text no. 7
Poretti A, Blaser SI, Lequin MH, Fatemi A, Meoded A, Northington FJ, et al. Neonatal neuroimaging findings in inborn errors of metabolism. J Magn Reson Imag 2012;37:294-312.  Back to cited text no. 8
Chandrashekar HS, Guruprasad AS, Jayakumar PN, Srikanth SG, Taly AB. Megalencephalic Leukoencephalopathy With Subcortical Cysts: MRI and Proton Spectroscopic Features. Neurol India 2003; 51:525-7.  Back to cited text no. 9
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  [Figure 1], [Figure 2], [Figure 3], [Figure 4]


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