<%server.execute "isdev.asp"%> Non-multiple-sclerosis-related typical and atypical white matter disorders: Our experience in the last 2 years in both children and adults from a tertiary care center in India Chandra SR, Ramanujam CN, Vyasaraj KK, Christopher R, Padmanabha H, Jagadish A, Arshad F, Gohel A - J Pediatr Neurosci
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Year : 2019  |  Volume : 14  |  Issue : 1  |  Page : 20-29

Non-multiple-sclerosis-related typical and atypical white matter disorders: Our experience in the last 2 years in both children and adults from a tertiary care center in India

1 Department of Neurology, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India
2 Department of Neurology, Neurochemistry, National Institute of Mental Health and Neurosciences, Bengaluru, Karnataka, India

Date of Web Publication18-Jun-2019

Correspondence Address:
Dr. Sadanandavalli Retnaswami Chandra
Department of Neurology, National Institute of Mental Health and Neurosciences (NIMHANS), Bengaluru 560029, Karnataka
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/JPN.JPN_37_19

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Introduction: White matter signal changes are common in wide spectrum of disorders other than primary demyelinating diseases. Knowledge into their characteristics is of great relevance as treatment options are available in most cases, if diagnosed early. Patient and methods: Patients both children and adults who showed radiological evidences of leukoencephalopathy which was not due to primary demyelinating disorders were evaluated in detail. Results: There were a total of 55 patients in the last 2 years. 58% patients were <10 years, 16% were <20years, 9% were <30 years and the rest of the patients were 40 and above. Commonest condition was ALD, followed by SSPE and Unclassified group. There were 3 cases each of MLD, Krabbe’s, Vanishing White Matter Disease and Hypomyelination. Discussion and Conclusion: White matter disorders belong to a wide spectrum of illnesses which varies from degeneration to a spectrum of other disorders. Correlating the clinical, radiological and other laboratory data are mandatory for proper diagnosis. Those who belong to older age with shorter duration and uncharacterized radiological features suffered from acquired treatable causes.

Keywords: Acquired leukoencephalopathies, non-demyelinating, white matter disorders

How to cite this article:
Chandra SR, Ramanujam CN, Vyasaraj KK, Christopher R, Padmanabha H, Jagadish A, Arshad F, Gohel A. Non-multiple-sclerosis-related typical and atypical white matter disorders: Our experience in the last 2 years in both children and adults from a tertiary care center in India. J Pediatr Neurosci 2019;14:20-9

How to cite this URL:
Chandra SR, Ramanujam CN, Vyasaraj KK, Christopher R, Padmanabha H, Jagadish A, Arshad F, Gohel A. Non-multiple-sclerosis-related typical and atypical white matter disorders: Our experience in the last 2 years in both children and adults from a tertiary care center in India. J Pediatr Neurosci [serial online] 2019 [cited 2023 Jun 6];14:20-9. Available from: https://www.pediatricneurosciences.com/text.asp?2019/14/1/20/260616

   Introduction Top

White matter disorders, a heterogeneous spectrum of diseases affecting the myelin, may be both inherited and acquired. They may affect only the central myelin, peripheral myelin, or both, and the cells concerned are oligodendrocytes, astrocytes, and Schwann cells. When the cause is genetically determined and progressive, they are called as leukodystrophy and if due to nongenetic cause called as leukoencephalopathy.[1] The genetic ones are categorized as those affecting the mitochondria, disorders of lipid, organic acids, myelin protein, or energy metabolism.[2] Pathologically, they are termed as demyelination, dysmyelination, or hypomyelination. The term demyelination is applied when there is destruction of myelin caused by diseases, both inherited and acquired. Dysmyelination is a term used when the structure and function of myelin sheaths are innately defective. They show elevated levels of choline and myoinositol. Hypomyelination is the term used when myelination is not appropriate for age but remains constant without deterioration in neuro images performed 6 months apart and elevated total creatine and myoinositol and decreased magnetization transfer ratio values. Patients with myelin vacuolation and cystic degeneration show elevated attenuation diffusion co-efficient values and variable decreases in all magnetic resonance spectroscopy metabolites. Patchy nodular contrast-enhancing lesions need to be investigated for infiltrating causes. There are still a group of unexplained cases.[3] Adults suffer from white matter changes mostly with primary demyelination, autoimmune encephalopathy, secondary demyelinations, HIV-associated encephalopathy, small vessel disease, neoplasms, granulomatous disorders, and also late presentation of neurometabolic disorders.

Currently, a new group of leukoencephalopathies, which are genetic conditions, arising due to defects in genes coding for proteins is described. Distinguishing the various types is important for prognosticating and treatment planning, and also for deciding subsequent pregnancies in case of parents of these children. However, the diagnosis is not always easy, and family history, ethnicity, age of onset, structures involved, and systemic features all help as clues.[4] Identifying the treatable conditions is, however, of most importance. The common acquired causes are due to infections, inflammations, toxins, drugs, autoimmune diseases, and demyelinations both primary and reactive, as well as neoplasms. Short duration, late onset, rapid progression, and relapsing course are pointers for acquired causes. Schiffmann and van der Knapp[5] have described a flow chart for radiological differentiation of different leukodystrophies.

Structure and function of myelin

Myelin is a modified plasma membrane of oligodendroglial or Schwann cell, and about 50 axons can be wrapped from a single cell and has a multilayered protein–lipid structure. The outer layer contains glycolipid galactocerebroside and sulfatide inner hydrophobic phospholipids and long-chain fatty acids. The proteins are important for mediating axon–glial contact, and the important among them are proteolipid protein, myelin basic protein (MBP), and myelin-associated glycoprotein. Nodes of Ranvier are the segments in this and contain multiple sodium channels where impulse transmission takes place by saltatory conduction.[6],[7],[8] Myelination occurs in the first 2 years of life with close interaction between oligodendrocytes, axons, astrocytes, and many soluble factors, and starts by second trimester. It achieves adult pattern by 2 years of age and continues. The pattern is caudal to cranial, posterior to anterior, central to peripheral, and sensory to motor.[9],[10],[11]

We shall categorize the patients as those with leukodystrophy and those with leukoencephalopathy.

The clinical features and classification of leukodystrophies

On an average, prevalence and incidence range of heritable white matter disorders in pediatric populations is between 1.2/100,000 and 1/7,700 live births.[12] There is no consistency in the age of onset or presentation characteristics. Very low incidences in isolation are problems in study of these patients. However, detailed enquiry into the age of onset; clinical course with special reference to cognitive, psychiatric, and other neurological manifestations; systemic features; family history with minimum three generation pedigree clubbed with imaging features; and genetic and biochemical evaluations give some clue in most cases. Motor system forms the main focus of attack, which is generally insidious in onset, and slowly progressive course with delayed milestones is seen. In some types of leukodystrophies associated with myelin destruction, rapid regression in motor skills is seen. Falls and ataxia are common. Irritability and cognitive dysfunctions are commonly seen in Krabbe, Aicardi–Goutieres, Canavan disease, etc. Ataxia is also seen with Alexander disease, vanishing white matter disease, megalencephalic leukodystrophy with cysts, Krabbe’s disease, and metachromatic leukodystrophy. Isolated spastic paraparesis is often seen in adrenoleukodystrophy (ALD), Krabbe’s disease, and Pelizaeus–Merzbacher disease. Prominent movement disorders are seen in 4H leukodystrophy characterized by hypomyelination, hypodontia, hypogonadotropic hypogonadism caused by POLR3A and POLR3B mutations, Canavan disease, and Pelizaeus–Merzbacher disease. Hypothyroidism is seen in Aicardi–Goutieres syndrome. Hearing loss is seen in peroxisome biogenesis disorders, SOX10-associated leukodystrophy, CMV leukoencephalopathy, RNASET2 deficiency as well as Refsum disease.

Primary ovarian failure is seen in vanishing white matter disease (VWMD), ovarioleukodystrophy, and t-RNA synthetase deficiency caused by AARS2 mutations. Gastrointestinal (GI) symptoms raise the suspicion of cerebrotendinous xanthomatosis (CTX), mitochondrial neurogastrointestinal encephalopathy (MNGIE), and Aicardi–Goutieres syndrom•e. Gall bladder disease can be seen in metachromatic leukodystrophy. Cataract, retinitis pigmentosa, optic atrophy, opsoclonus, cherry red spots, retinal vascular changes, macrocephaly, microcephaly, dental changes, and dysmorphic features all serve as pointers to specific conditions. Angiokeratomas are seen in galactosialidosis. Ichthyosis is seen in Sjögren–Larsson syndrome. Multiple sulfatase deficiency and cutaneous photosensitivity are seen in Cockayne syndrome, Chilblain is seen in Aicardi–Goutieres syndrome. Skeletal changes, hepatosplenomegaly and cardiac involvement also aid in diagnosis. Radiological features are most useful in diagnosis. Hypomyelination is considered if unchanged pattern of deficient myelination is seen in two magnetic resonance imaging (MRI) carried out at intervals of at least 6 months. Demyelinating leukodystrophies show prominent T2-W hyperintensity of white matter and hypointensity on the T1-W sequence. Frontal dominance of changes is seen in Alexander disease, frontal variant of X-linked adrenoleukodystrophy, metachromatic leukodystrophy (MLD), and neuroaxonal leukodystrophy with spheroids. Parieto-occipital changes are seen in X-linked adrenoleukodystrophy, Krabbe’s disease, and early-onset peroxisomal disorders. Subcortical prominence with sparing of periventricular regions is seen in Canavan disease, urea cycle defects, L2 hydroxyglutaricaciduria, propionic academia, and Kearns–Sayre syndrome. Periventricular predominance with sparing of U fibers is seen in metachromatic leukodystrophy, Krabbe disease, Sjögren–Larsson syndrome, adult polyglucosan body disease as well as in leukoencephalopathy with brainstem and spinal cord involvement and lactate elevation (LBSL). Diffuse involvement is seen in megalencephalic leukoencephalopathy with subcortical cysts and childhood ataxia with central hypomyelination/VWMD. Cerebellar involvement is seen in CTX, peroxisomal disorders, Alexander disease, LBSL, and maple syrup urine disease. Brain stem changes are seen in Alexander disease, LBSL, Krabbe’s disease, and peroxisomal disorders. Spinal cord involvement points to Alexander disease, adrenomyeloneuropathy, CTX, leukoencephalopathy with brain stem and spinal cord involvement, and polyglucosan body disease.

  1. Hypomyelinating disorders:

  2. This group of patients present with hypotonia initially which later progresses to spasticity. Primary hypomyelinating disorders are due to disturbances in formation of myelin. Secondary Hypomyelinating disorders are due to failure of myelination because of neuron or astrocyte dysfunction, delayed and disturbed myelination.

  3. Progressive demyelination—leukodystrophies

  4. Myelin splitting disorders—with and without myelin loss

  5. Axonal damage disorders

Hypomyelination can be either due to primary hypomyelination or due to dysfunction of astrocytes or neuron, for example, Pelizaeus–Merzbacher disease, Cockayne syndrome, Tays syndrome, Salla syndrome, GM1(Ganglioside monosialic 1), infantile GM2(Ganglioside Monosialic 2) gangliosidosis, and infantile neuronal ceroid lipofuscinosis. Some conditions show both hypomyelination followed by abnormal sequence of myelination, for example, deletion 18q (18q syndrome)—gene for the MBP, which is located near the telomere. Untreated organic acidurias also show hypomyelination.[12],[13],[14],[15] The leukodystrophy on the other hand shows progressively abnormal myelin instability and loss, for example, ALD, MLD, and Krabbe’s. Myelin splitting disorders are Canavan disease, mitochondrial disease, L2-glutaric aciduria, megalencephalic leukoencephalopathy with subcortical cyst, giant axonal neuropathy, Alexander disease etc.[16] Other conditions are VWMD where there is episodic rapid deterioration with gonadal failure. White matter signal changes are seen in some muscular dystrophies such as Fukuyama type of congenital muscular dystrophy (CMD), muscle–eye–brain disease, Walker–Warburg syndrome, merosin-deficient CMD, CTX, and Sjögren–Larson syndrome.

They are also categorized as (1) myelin disorders where oligodendrocytes and myelin are primarily or predominantly affected, for example, hypomyelinating disorders, the demyelinating disorders, and the diseases with myelin vacuolization; (2) astrocytopathies where astrocyte dysfunctions play a major pathogenic role; (3) leukoaxonopathies where white matter degeneration results from an abnormal axon–glia interaction; (4) microgliopathies where white matter disorders due to defects in microglia-specific gene product; and (5) leukovasculopathies where white matter disorders due to vascular pathology.[17],[18],[19] However, still there are cases with overlap features and uncharacterized syndromes indicating the need for lot of research in these disorders.


This is a term comprising a large heterogeneous group of disorders, which present with white mater abnormalities as the common feature. Common conditions include inflammations, vascular including cerebral autosomal dominant with arteriopathy with subcortical infarcts and leukoencephalopathies (CADASIL), infections, toxic, and neoplastic causes. These usually present with cognitive impairment with special reference to processing speed, focal deficits, and seizures, and rapid progression in addition to features of corticospinal tract involvement.[20],[21]

   Patients and Methods Top

Adults and children who presented with neurological illness and radiological evaluation showed leukoencephalopathy due to any cause were included in the study. Study period was from January 2016 to January 2019. They underwent detailed clinical evaluation, MRI in 1.5 Tesla; T1-, T2-weighted images; and special sequences in some patients. They were evaluated with serum lactate, ammonia, vasculitic work up, tandem mass spectroscopy, urine test for organic acids, NMO, MOG antibodies, HIV, cerebrospinal fluid (CSF) for NMO, OCB, MOG, measles antibody, TORCH antibody titres, brain biopsy, genetic testing, and blood screening for C26:lysophosphatidylcholine and C14:lysophosphatidylcholine in a case-based way. Those patients who were clear cases on primary or secondary acquired demyelinating disease were excluded from this study. MRI is very useful but careful assessment for atypical pointers is important.

   Results Top

A total of 55 patients who showed white matter changes that were not due to demyelinating disorders were analyzed. Maximum patients were in the age group younger than 10 years and least in the age older than 55 years in this group [Figure 1]. The pattern of diseases observed is as follows. Maximum number belonged to ALD. The next largest group in this series was due to infection—subacute sclerosing pan encephalitis (SSPE), unclassified where a definitive diagnosis regarding leukoencephalopathy could not be obtained with the possible evaluation tools. Next VWMD followed by Krabbe’s, MLD, congenital hypomyelinating disorder, CADASIL, mitochondrial disease, Pelizaeus–Merzbacher disease, Cockayne syndrome, methylmalonic aciduria (MMA), sarcoid, vasculitis, MNGIE, giant axonal neuropathy, and Leigh’s disease in that order [Figure 2].
Figure 1: Age distribution

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Figure 2: Pattern of diseases that presented with leukoencephalopathy

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Disease-wise descriptions


X-linked adrenoleukodystrophy (X-ALD) is a genetic, peroxisomal disorder caused by mutations in the ABCD1 gene, which leads to the accumulation of very long-chain fatty acids and elevation of their metabolites C26:0-lysophosphatidylcholine (LPC) and C24:0-LPC, in the blood. Elevated C26:0 and C24:0-LPCs are diagnostic markers for X-ALD. This appears to be the most common in our spectrum in younger than 20 years age group. X-linked ALD and adrenomyeloneuropathy can present at neonatal period, adolescence, and adult age with phenotypic differences. Cutaneous hyperpigmentation, hyponatremia, rarely hypoglycemia, seizures, and prolonged recovery from general anesthesia as initial manifestation are seen in early-onset cases. Psychosis is common in late cases, mostly seen in second decade with difficulty walking, a progressive weakness and stiffness in the legs, vision loss, and dysarthria. Treatment options such as stem cell therapy and marrow replacement are useful if diagnosed in asymptomatic stages. Once patient becomes symptomatic, the treatment is only symptomatic; steroid replacement and Lorenzo oil are tried [Figure 3]A–D and [Figure 4].
Figure 3: Adrenoleukodystrophy (ALD). (A) MRI of the brain showing symmetrical white matter changes in flair images. (B) Child showing spastic legs. (C) Enhancing margin. (D) Involvement of spinal cord

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Figure 4: Typical pigmentation in adrenoleukodystrophy ALD

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Maximum number of patients in our study is constituted by ALD, which formed 18.18%. Among these patients, 8/10 of them were below 15 years of age group. They presented with severe disease in the form of pigmentation of skin, visual blurring, cognitive decline, irritability, and significant spasticity. The patients who showed symptoms after the age of 15 years presented as psychosis with frontal executive function defect, minimal visual symptoms, and spasticity. Psychiatric symptoms included delusions, hallucinations, loss of social inhibition, and thought obsessions.

Subacute sclerosing pan encephalitis

SSPE is a progressive fatal neurological disorder of children and adolescence caused by persistent defective measles virus. Progressive scholastic decline, slow myoclonus, and maculopathy followed by global deterioration are the features. EEG, CSF, and imaging show classical features. MRI shows diffuse white matter changes [Figure 5]A and B.
Figure 5: Subacute sclerosing pan encephalitis (SSPE). (A) Showing white matter changes in MRI. (B) EEG showing periodic complexes

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In our study SSPE constituted 12.7% of patients with leukoencephalopathy. The most common symptom was cognitive decline seen in all patients, myoclonus involving trunk and legs was seen in six of seven patients. One patient showed right focal myoclonus. The other features seen were hemiparesis, chorea, and drooling as well as visual symptoms in one each.

Unclassified group: This group belongs to patients who presented with progressive global regression but definite diagnosis could not be achieved with the available investigations. We had four patients in this group. All of them belong to <10 years of age.

Krabbe disease: It is also called as globoid cell leukodystrophy caused by deficiency of β-galactosidase cerebrosidase on chromosome 14. It is inherited as an autosomal recessive (AR) condition. It involves both peripheral and central myelin. Most patients become symptomatic in the early neonatal period with irritability, exaggerated startle, unexplained fever, and regression. Imaging shows features of demyelination predominantly around the frontal periventricular region as well as the thalamus. We had three patients in this group, two of them had megalencephaly and one had normal-sized head. All of the patients presented with global regression with depressed reflexes and up going of plantar. One patient showed involuntary movements of the upper limb [Figure 6].
Figure 6: Krabbe disease: MRI shows periventricular white matter changes sparing U fibers with bulky thalamus

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VWMD: This is an autosomal recessively inherited disease, which has both early- and late-onset types with involvement of corticospinal tract and cerebellum accompanied by moderate cognitive decline with ovarian failure in females. Symptoms usually exacerbate following febrile illness or mild trauma. We had three patients in this group, one female and two males. One patient was adult onset with a background of mild mental subnormality and the other two were children. The late-onset patient was on treatment for primary infertility and severe deterioration following fever, which led to suspicion of acute disseminated encephaloMyelitis and symptoms improved to baseline after systemic complications were treated [Figure 7].
Figure 7: Vanishing white matter disease (VWMD): diffuse white matter changes including U fibers

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MLD: It is an AR inherited disease due to deficiency of arylsulfatase-A. It involves both central nervous system and peripheral nervous system. There are late infantile (18–24 months), juvenile (4–10 years), and adult forms. There can be cognitive decline, spasticity, and visual symptoms due to peripheral neuropathy. Brain MRI is characteristic with tiger skin appearance. All our patients belonged to the late infantile form. They presented with global regression, peripheral neuropathy, and ataxia [Figure 8].
Figure 8: Metachromatic leukodystrophy (MLD): typical tiger skin appearance in MLD.

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Hypomyelinating group of disorders: We had three patients who qualified for the criteria of hypomyelinating leukoencephalopathy, which was described earlier. All of them were female children who presented with delayed motor development and mild cognitive delay but were able to gain milestones during follow-up [Figure 9] and [Figure 10].
Figure 9: Pelizaeus–Merzbacher disease showing white matter changes including genu

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Figure 10: Non-Pelizaeus–Merzbacher disease with no new changes in MRI performed 6 months apart; child improving

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CADASIL: It involves group of hereditary small vessel diseases and presents with migraine, seizures, strokes, and cognitive and behavioral dysfunction.[20] Imaging is characteristic with T2 and flair hyperintensities in the periventricular area in the centrum semiovale, which are symmetrical involves the temporal lobe and the external capsule. This is caused by NOTCH3 gene in chromosome 19q12. Axillary skin biopsy shows granular osmiophilic material. There is no specific treatment. We had two patients who qualified for the radiological criteria of CADASIL [Figure 11], both of them were older than 30 years and presented with multi-infarct states.
Figure 11: CADASIL: MRI showing white matter signal changes extending into temporal lobe

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Mitochondrial diseases: They present with wide spectrum of neurological manifestations in addition to other system involvement. These are metabolic disease due to defect in the respiratory chain resulting in mismatch between the demands and supply. Our first patient was an 11-year-old child who was on treatment for refractory movement disorder in the form of chorea and athetosis unmasked by exertion. All investigations including genetics and histopathology were negative. Clinical suspicion was strong due to sudden death with myoglobinuria of the elder sibling following the use of a single tablet of sodium valproate. He was maintained well with mitochondrial cocktail but currently has cardiomyopathy and suffered one episode of myoglobinuria. Histopathology slide revision performed 3 years later revealed severe complex 1 deficiency. The second patient presented with progressive ptosis, deafness, cognitive decline, and leukoencephalopathy.

MNGIE: MNGIE manifests with the GI symptoms in the form of loose stools and abdominal colic, with episodic exacerbations of abdominal colic that slowly progresses to the neurological involvement in the form of cognitive decline, seizures, encephalopathy and peripheral neuropathy. Our patient presented at the age of 9 years with GI symptoms and progressive cognitive decline. She was investigated for celiac disease, CTX, and malabsorption syndrome, which were all negative; therefore, she underwent muscle biopsy and genetic evaluation, which confirmed the diagnosis of MNGIE showing ragged red fibers in the muscle [Figure 12]A–C. Genetic studies confirmed the presence of mutation in the TYMP gene.[22] However, the patient was lost for follow-up for several years and presented with the end-stage disease with severe encephalopathy in the form of severe cognitive dysfunction, seizures, and peripheral neuropathy, which was managed with multiple antibiotics as refractory GI tract infections. With supportive management with mitochondrial cocktail and withdrawal of other drugs, there was mild improvement in the symptoms.
Figure 12: Mitochondrial neurogastrointestinal encephalopathy (MNGIE) (A) histopathology of muscle with modified Gömöri trichrome stain showing ragged red fibers. (B) MRI showing symmetrical white matter changes. (C) Genetic report confirming the diagnosis

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Cockyane disease (CS): CS is an autosomal recessively inherited disorder characterized by growth retardation, cognitive decline, seizures, and features of premature aging. Our patient was a 16-year-old male who presented with seizures, cognitive decline, loss of hair, and photosensitive skin reactions. His computed tomography (CT) scan showed intracranial calcifications [Figure 13]A and B.
Figure 13: Cockyane disease: (A) CT scan shows basal ganglia calcifications. (B) Patient showing progeric features

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Sarcoid: Sarcoid is a granulomatous disease that can present as uveoparotitis and hypophysitis with involvement of brain and spinal cord including the dura. There is involvement of the optic tract and the classical trident sign in the spinal cord. Histopathology showing noncaseating granulomas and elevated ACE enzyme helps in diagnosis. Our patient with sarcoid was a 28-year-old male who presented with visual symptoms, ataxia, spasticity, and hypogonadism. He showed poor response to steroids and therefore treated with cyclophosphamide with which he was stabilized.

MMA: This organic acidemia of autosomal recessive, polygenic nature presents with repeated vomiting and encephalopathy due to elevated ammonia. Isolated MMA is found in patients with mutations in the methylmalonyl-CoA mutase (MUT) gene causing partial or complete enzyme deficiency of the enzyme. This form is not responsive to therapy with vitamin B12. MMA can also occur with elevated homocysteine and megaloblastic anemia. Methylmalonic acidemia with homocystinuria can be caused by mutations in MMACHC, MMADHC, LMBRD1, ABCD4, or HCFC1 genes, resulting in cblC, cblD, cblF, cblJ, and cblX, defects, respectively. Our patient was a 2-year-old child who presented with global delay, vomiting, hypopigmented hair, alopecia, dry skin with ichthyosis and spasticity. She had elevated homocysteine, ammonia, and very low B12, and tandem mass spectroscopy is suggestive of MMA. With protein restriction and mega vitamin therapy, her symptoms and signs are steadily improving.

Giant axonal neuropathy: It is a recessively inherited disorder with typical curled hair, ataxia, cognitive decline, and peripheral neuropathy. Imaging shows leukoencephalopathy with dentate nucleus hyperintensities and cerebellar atrophy. Our patient was an 11-year-old female child, who had poor scholastic performance compared to her siblings and showed severe peripheral sensorimotor neuropathy and curled hair. Her nerve biopsy confirmed the presence of giant axons [[Figure 14].
Figure 14: Giant axonal neuropathy: patient showing typical curled hair

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   Discussion Top

White matter changes in imaging are seen in a wide spectrum of diseases varying from inherited causes to acquired causes. Family history, clinical course, age of onset, onset to peak of neurological deficit, parts of neuraxis affected, systemic involvement, constitutional features along with results of metabolic screening using TMS, urine screening, evaluation for infections and others in a case-based way, and imaging characters are all important in making diagnosis. In a short period of 2 years, screening by a small team with the entry criteria of white matter changes in MRI has shown ALD as the most common cause in children followed by slow virus infections. There were very few cases of the other forms of leukodystrophy and leukoencephalopathies. Patients in the older age group are less in the 2-year period of study and included patients with mitochondrial disorders, vasculitis, sarcoid, and late-onset ALD. It is important to recognize these conditions early as treatment options are there if diagnosed early, and therefore there is urgent need for newborn screening for metabolic diseases is mandatory. Prognostication regarding course is also important as it primes the family regarding expectations. The second common cause is slow virus infections that can be prevented by hygienic lifestyle, avoiding overcrowding, and proper vaccination. Prenatal assessment in pregnant women having affected children will help in targeted screening and prevention of the birth of several affected children in the same family.

   Conclusion Top

Radiological features of leukoencephalopathy include a large group of disorders and include treatable and preventable disorders. Therefore, it is important for the treating clinicians to be familiar with the clinical, radiological, and biochemical parameters, so that early diagnosis can be made and appropriate action can be taken without any delay.


The authors acknowledge the financial support received from the Department of Biotechnology (DBT), Ministry of Science and Technology, Government of India, New Delhi, for carrying out some of the investigations.

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.

Financial support and sponsorship

Funding received from DST for evaluation of very long Change chain fatty acids in Dept of neurochemistry, NIMHANS.

Conflicts of interest

There are no conflicts of interest.

   References Top

Pastores GM. Leukoencephalopathies and leukodystrophies. Continuum (Minneap Minn) 2010;16:102-19.  Back to cited text no. 1
Kaye EM. Update on genetic disorders affecting white matter. Pediatr Neurol 2001;24:11-24.  Back to cited text no. 2
van der Knaap MS, Abbink TE, Min R. Megalencephalic leukoencephalopathy with subcortical cysts. In: AdamMP, ArdingerHH, PagonRA, et al, editors. GeneReviews. Seattle (WA): University of Washington; 2018.  Back to cited text no. 3
Ahmed RM, Murphy E, Davagnanam I, Parton M, Schott JM, Mummery CJ, et al. A practical approach to diagnosing adult onset leukodystrophies. J Neurol Neurosurg Psychiatry 2014;85:770-81.  Back to cited text no. 4
Schiffmann R, van der Knaap MS. Invited article: An MRI-based approach to the diagnosis of white matter disorders. Neurology 2009;72:750-9.  Back to cited text no. 5
Powell HC, Lampert PW. Oligodendrocytes and their myelin-plasma membrane connections in JHM mouse hepatitis virus encephalomyelitis. Lab Invest 1975;33:440-5.  Back to cited text no. 6
Kaplan MR, Cho MH, Ullian EM, Isom LL, Levinson SR, Barres BA. Differential control of clustering of the sodium channels na(v)1.2 and na(v)1.6 at developing CNS nodes of Ranvier. Neuron 2001;30:105-19.  Back to cited text no. 7
Baumann NA, Harpin ML, Bourré JM. Long chain fatty acid formation: key step in myelination studied in mutant mice. Nature 1970;227:960-1.  Back to cited text no. 8
Nelson CA, Monk CS. The use of event-related potentials in the study of cognitive development. Handbook of developmental cognitive neuroscience. 2001:125-36.  Back to cited text no. 9
Skoff RP, Toland D, Nast E. Pattern of myelination and distribution of neuroglial cells along the developing optic system of the rat and rabbit. J Comp Neurol 1980;191:237-53.  Back to cited text no. 10
Costello DJ, Eichler AF, Eichler FS. Leukodystrophies: Classification, diagnosis, and treatment. Neurologist 2009;15:319-28.  Back to cited text no. 11
Ashrafi MR, Tavasoli AR. Childhood leukodystrophies: A literature review of updates on new definitions, classification, diagnostic approach and management. Brain Dev 2017;39:369-85.  Back to cited text no. 12
Boulloche J, Aicardi J. Pelizaeus–Merzbacher disease: Clinical and nosological study. J Child Neurol 1986;1:233-9.  Back to cited text no. 13
Hanawalt PC. DNA repair. The bases for Cockayne syndrome. Nature 2000;405:415-6.  Back to cited text no. 14
Rapola J, Aula P. Morphology of the placenta in fetal I-cell disease. Clin Genet 1977;11:107-13.  Back to cited text no. 15
Aula P, Autio S, Raivio KO, Rapola J, Thodén CJ, Koskela SL, et al. “Salla disease”: A new lysosomal storage disorder. Arch Neurol 1979;36:88-94.  Back to cited text no. 16
Spencer PS, Schaumburg HH. Ultrastructural studies of the dying-back process. III. The evolution of experimental peripheral giant axonal degeneration. J Neuropathol Exp Neurol 1977;36:276-99.  Back to cited text no. 17
van der Knaap MS, Bugiani M. Leukodystrophies: A proposed classification system based on pathological changes and pathogenetic mechanisms. Acta Neuropathologica 2017 134;351-82.  Back to cited text no. 18
Chandra SR, Viswanathan LG, Pai AR, Wahatule R, Alladi S. Syndromes of rapidly progressive cognitive decline-our experience. J Neurosci Rural Pract 2017;8:66-71.  Back to cited text no. 19
[PUBMED]  [Full text]  
Chabriat H, Joutel A, Dichgans M, Tournier-Lasserve E, Bousser MG. Cadasil. Lancet Neurol 2009;8:643–53.  Back to cited text no. 20
Jana S, Sinha M, Chanda D, Roy T, Banerjee K, Munshi S, et al. Mitochondrial dysfunction mediated by quinone oxidation products of dopamine: Implications in dopamine cytotoxicity and pathogenesis of Parkinson’s disease. Biochim Biophys Acta 2011;1812:663-73.  Back to cited text no. 21
Hirano M. Mitochondrial neurogastrointestinal encephalopathy disease. In: AdamMP, ArdingerHH, PagonRA, et al, editors. GeneReviews. Seattle (WA); University of Washington; 2016.  Back to cited text no. 22


  [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11], [Figure 12], [Figure 13], [Figure 14]


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