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Mizuguchi M. Br. Dev. 1997;19:81-92.

Neilson DE et al. Neurol.2003;61:226-30,

Neilson DE et l. Ann Neurol.2004;55:291-94

Neilsen DE et al. Am J Hum genet 2009 Jan;84(1):44-51

Most ANE is sporadic and nonrecurrent

Recurrent ANE is an incompletely penetrant, autosomal-dominant trait.

Even familial cases have de novo origin.

Most begin in childhood but some may have onset in the 2nd to 4th decade, mistaken for MS.

Missense mutations identified in the gene encoding the nuclear pore protein Ran Binding

Protein 2 (RANBP2),

RANBP2 is a nuclear pore complex protein (Nup358)-358kD located at Chr 2q12.3

Its roles a) protein import and export and sumoylation

b) Intracellular trafficking (microtubules) and energy metabolism (mitochondria)

c) during mitosis facilitates sister chromatid resolution

Neilsen DE et al. Am J Hum genet 2009 Jan;84(1):44-51. Am J Hum genet 2009

Acute Necrotizing Encephalopathy (ANE)

Mutations were noted in 75% of cases and not in 25% with recurrent or familial

disease, so the authors suggest calling these familial or recurrent cases as ANE1.

There are isolated non-familial cases of ANE without mutations in RANBP2.

Similarities with ANE1 were

a) preceding infection b) seizures,

c) coma d) ↑CSF protein e) MRI.

However, these patients had elevated LFT.

Neilsen DE et al. Am J Hum genet 2009 Jan;84(1):44-51

Acute Necrotizing Encephalopathy (ANE) Novel Leukoencephalopathies with Calcifications

RNASET2 gene defect

Aicardi Goutieres syndrome

Cerebroretinal microangiopathy with calcifications and cysts (CRMCC).

Recessive developmental delay, small stature, microcephaly and brain calcifications with locus on chromosome 2

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Cockayne Syndorme

Muftuoglu M: Gene 2002 Jan 23; 283(1-2):27-40

CMV Infection

Bale JF: Pediatr Clin

North Am. 1992; 39:

669

CMV Infection

Bale JF: Pediatr Clin

North Am. 1992; 39:

669

RNASET2-deficient

Cystic

leukoencephalopathy

resembles congenital

CMV brain infection

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Human RNASET2 protein enters the secretory pathway and is secreted

CMV seems to be involved in chronic vascular disease.

A role in angiogenesis is also described for RNASET2.

After CMV infection, activation of human RNase L by oligoadenylate synthetases is

a known antiviral response to degrade viral and cellular ss RNAs, which the virus

tries to block as an evasion strategy.

During brain development, both an inborn failure of RNASET2 activity or the

prevention of Rnase L activation by CMV would result in raised levels of ssRNA,

stimulating a comparable immune response

CMV Like cystic LeukoencephalopathyAicardi-Goutieres Syndrome

Autosomal Recessive inheritance

Early onset encephalopathy, szs, thrombocytopenia, organomegaly, fever, chilblains

CSF: WBC (>5),interferon-alpha (>10pg/ml),pterins (neopterin), Respond to folinic acid if low in CSF MTHF

Calcifications: basal ganglia & in tissues and perivascular cuffs with microinfarcts-microangiopathy

Gene defects: 127 pedigrees:Trex1 (32),H2A (5),H2B (50),H2C (18),Unknown (22)

TREX1 AGS1-3p21(Cree encephalitis) exonuclease excises nucleoside monophosphates from 3’->5’DNA, caspase independent apoptosis

RNAse H2 : cleaves RNA from RNA:DNA or DNA:DNA duplexes

AGS 2 (13q14-21, RNAse H2B, AGS 3 (11q13.2 RNAs H2C) AGS 4 ( 19p13.13 RNAse H2A), suspected AGS 5,

Mutations: TREX1 and H2 complexes impair enzymatic activity involved in proof reading & processing of DNA & RNA. clearance of anomalous DNA/RNA triggers immune response

Crow YJ et al: Nat Genet.: 2006: 38: 917-920, Crow YJ et al: Nat Genet.: 2006: 38: 910-916, Rice G et al: Am J hum genet.: 2007: 80:811

Aicardi-Goutieres Syndrome TREX1 gene defect: homozygous c.341 g>a R114H .

A mutation common in patients of European originAicardi-Goutieres Syndrome

Aicardi J: Ann Neurol. 1984; 15: 49

Goutieres F: Ann Neurol. 1998; 44: 900

Barth PG: Acta Neuropathol (Berl) 1999; 98: 212

Crow YJ: Am J Hum Genet. 2000; 67 :213.

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Labrune disease

Labrune P: Neurology. 1996; 46: 1297

Cerebroretinal microangiopathy with calcificationsand cysts (CRMCC).

Recessive developmental delay, small stature, microcephaly and brain calcifications with locus on chromosome 2

Anna Rajab et al Am J Med Genet 2010: 149A:129-137

Thin Anterior Corpus Callosum,and Leukoencephalopathy-SPG11

Thin anterior corpus callosum & Leukoencephalopathy-SPG1130 yr Male

DV (30) DN (28) DR (26)

Learning disability 3-5 3-5 3-5

HC >98% 98% 90%

Spastic/contract 13 17/+ 16/++

Wheel Chair 27 21 18

Dysarthria +/tongue fasics aphonic aphonic

Mm Wasting distal distal distal & prox

Per. Neuropathy + + +

Vasomotor abn/LE – + ++

Bladder/Bowel – – –

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THIN ANTR. CORPUS CALLOSUM, LEUKOENCEPHALOPATHY

NERVE AND SKIN BIOPSY

Spastic Paraplegia with Thin Corpus Callosum SPG 11

Stevanin G et al: Nat Genet: 2007: 39: 366-372

Autosomal recessive hereditary spastic paraplegia (ARHSP) + TCC

Spasticity: Begins from infancy-puberty,

Central: Insidiously progressive dementia, dysarthria, dysphagia,

Systemic: Gradual to rapid progression of spasticity,

axonopathy: motor & sensory

Neuroimaging: MRI-thin rostral CC,

hyperintense WM- periventricular, frontal & occipital,

cortical atrophy frontal & thalamic,

PET scans: glucose in cortex and thalamus

Gene defect: 15q21.1

KIAA1840 (FLJ21439), (40 exons),

missense,deletions, insertions,

spastacsin - dioxygenase superfamily, 4 transmembrane

domains localizes to cytosolic, perinuclear and nuclear regions,

membranes, cytoskeleton, not seen in newborn rat brain

Spatial expression of KIAA1840 in adult mouse brain

Expression profile of KIAA1840 by RNA blot in adult human brain

Stevanin G et al: Nat Genet: 2007: 39: 366-372

A B

5.5 yr Male

Progressive Cavitating Leukoencephalopathy

Naidu et al: Ann Neurol:2005;58:929-938

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PCL: Pt 2 SC

Female

Sib/Pt1

Ages 3, 5&7 yrs

1991

1994

1996

A B

C

D

F 31 m

PCL

Progressive Cavitating Leuko-encephalopathy

M.S. Van der Knaap et al: Ann Neurol 53 (2003), pp. 252–258.

Scheper GC et al: Mitochondrial aspartyl-tRNA synthetase deficiency causes leukoencephalopathy with brain stem and spinal cord involvement and lactate elevation. Nat Genet. 2007 39:534-9.

Leukoencephalopathy with brainstem and spinal cord involvement, and lactate,

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MRS in Leukoencephalopathy with brainstem and spinal cord involvement and lacticacidosis

Neonatal porencephaly and adult stroke related to mutations in collagen IV A1

van der Knaap et al. Ann Neurol. 2006 Mar;59(3):504-11

Neonatal porencephaly and adult stroke related to mutations in collagen IV A1

van der Knaap et al. Ann Neurol. 2006 Mar;59(3):504-11

Deficiency of hyccin, a newly identified membrane protein, causes hypomyelination and congenital cataract

Federico Zara et al: Nature Genetics 2006 - 38, 1111 - 1113

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Leukoencephalopathy with ataxia, hypodontia and

hypomyelination

N. I. Wolf et al: Neurology 2005;64:1461-4

Cerebellar and Brainstem Leukodystrophy

with Basal Ganglia Involvement

Nl pre, peri, and postnatal history

Nl growth and development until 12 years.

School grades A’s abd B’s

12 years: Insidious onset of gait disturbance, slurred speech,

behavior problems including large ingestion of Tyelenol,

School grades dropped to D’s and F’s

Neurological exam: No nystagmus, rigidity, dystonia, ataxia,

DTR’s, bil. Babinski’s

Nl Evaluations: SCA, DRPLA, lysosomal disorders, AFP, NPC, Mito

DNA, Mm & skin bx, cobalamine deficiency, Fragile X

CDG, Cholestanol, Immunological, AA, Organic acids,

VLCFA, EMG/NCV, EKG

Nl CSF: protein sugar cultures, amino acids, immunology,

MBP, OL bands

10/1/96 T2 WI (top) and post-contrast T1 WI (bottom): 14 years

5/10/99

17 years

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Flair

T2

T14/29/05 23 years

Patient 2:

20 yrs

Similarities in established disorders

Metachromatic Leukodystrophy

Patient 1

Patient 2

Holve S et al. Am J Med Genet 2001;101: 203Gieselmann V et al. J Inherit Metab Dis 1998; 21:564Faerber EN et al. Pediatr Radiol 1999;29:669-72

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Late infantile onset MLD

PATTERN 1Parieto-occipital

lobe or splenium 63%

PATTERN 2Frontal lobe or

genu 17%

PATTERN 3Fronto-pontine-

corticospinal tracts 14%

Different anatomical patterns involved in cerebral X-linked Adrenoleukodystrophy

X-linked Adrenoleukodystrophy Krabbe Disease

Farina L et al. AJNR 2000;21:1478

Zarifi MK: J Child Neurol 2001;16: 522Wenger DA: Metabolic and Molecular Basis of Inherited Disease: 2001; Ed. 8: Vol 3: Chapter 147: 3669

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Prashanth LK et al. J Neurol Sc 2010;291:44

Wilsons Disease Prashanth LK et al. J Neurol Sc 2010;291:44

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Atherosclerosis Risk in Community (ARIC) Study

White Matter Lesion scale* 10 point scale (0:normal, 9 : maximal involvement)

standardized in more than 2000 controls

healthy normotensive individuals (mean age: 60 years)0: 15%

1: 53%

2: 24%

3-9: 7.6%

*Stroke 1996, 27:2262-70MRI in clinically/neurologically normal individuals

MRI in clinically/neurologically normal individuals

MRI in clinically/neurologically normal individuals

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PMD-Like disease in MCT8 mutated male subjects. Delayed

myelination

Catherine Vaurs-Barrie`re et al

Ann Neurol. 2009;65:114

monocarboxylate transporter 8 gene (MCT8, or SLC16A2, X-linked

1)Severe: early-onset hypotonia, nystagmus,dystonic movements, spastic quadriplegia, Milder forms exist

2)Abnormal thyroid hormone transporter function is increased free triiodothyronine (T3), low free thyroxine (T4), and normal thyroid-stimulating hormone (TSH) levels in the serum.

3) MCT8 mutations induce a deficiency in T3 cell entry despite high circulating T3 levels. No neurological improvement even with a T4 substitutive therapy confirms the need for T3 in the brain. Based on neuronal Mct8 expression in mice, a defect in T3 hormone in neurons is responsible for the severe mental and motor deficiencies in MCT8-deficient patients.

Leukoencephalopathy in 21-β hydroxylase deficiency:

mother

Proband 27 years: virilism, clitoral reduction, melanosis,

deep voice, weakness right side with hyperreflexia and Babinski, postural tremor of upper limbs, and ataxia father

Gaudiano C et al: Br & Devel. 2010;32:412

21-Hydroxylase deficiency is the most common cause of congenital adrenal hyperplasia. Autosomal recessive : due to impaired cortisol synthesis from cholesterol by adrenal cortex.Carrier parents also show signs of leucoencephalopathy. White matter anomalies may be present in carriers of a mutation in the CYP21 gene. Therefore authors suggest performing CYP21 gene analysis in subjects with brain MRI evidence of white matter abnormalities that cannot otherwise be explained.

Dysmorphism

YesNo

OrganomegalyInfections

No Yes

Cytologic Abn,Chromosome18q -,

Oculodental Digital Syndrome(GJA1 gene defect),

CDG *,Sotos *

Molybdenum cofactor deficiency

No Yes

Fucosidosis,Sialuria,

MPS

Peroxisome- biogenesis defects,GM1 gangliosidosis

Yes

No

ADEM,RANBP2 gene defectHemophagocyticlymphohistiocytosis(infectious)

calcificationsHIVCMV

Skin Abn

No Yes

Light Sensitive

No

Cockayne,Tay Syndrome,

Ataxia-Telangiec tasia*

Yes

Hypomelanosis of Ito,NF1 (UBO) *,

Sjogren - Larson,Multiple Sulfatase Deficiency

CTX

MRI Location

Supratentorial

YesNo

InfratentorialCentral pontine myelinolysisPeroxisomal biogenesis defects*,CTX, Alexander disease,Heroin Sniffing, DARS2 gene defect

Diffuse

Megalencephaly

Yes

No

Anterior

Retinal Abn

Yes

No

Canavan,MLC 1

Merosin deficiency*CACH/VWM, Cobalamine, Mitochondrial disorders,Polyglucosan body disease,Walker Warburg, Adult onset autosomal dominant leukodystrophy, muscle eye brain, Fukuyama, AGS, Wilsons disease, Toxins

Cystic changesPCL, Hemophagocyticlymphohistiocytosis (perforin gene defect & infectious), Col4A1 gene defect, Molybdenum cofactor defect

Yes No

Megalencephaly

Yes No

AlexanderSPG 11

MLD,X-ALD,Wilsons

Posterior

Yes No

X-ALD, Krabbe, CTX, Alexander,DARS2 gene defect

Periventricular

No

Yes

U fiber involvement,L2- Hydroxyglutaric

aciduria

HIE, MLD, PKU, MSKrabbe, Glutaric aciduria,

NCL- Infantile/late infantile formsCADASIL/Binswanger

Suggested Algorithm for Clinical Correlates of MRI White Matter Abnormalities

* Not Obligatory

calcifications

No Yes

AGS, RNASET2 gene defectLabrune diseaseNasu-HakolaCockayne, CTX, HIEOccipital calcification & strokes

PMD, PMD-like ,Sialuria, Hashimoto’s thyroiditis, hypomyelination & atrophy of basal ganglia & cerebellum, With dentition anomalies, With cataracts -(hyccin gene defect)mt. RRM2B gene defectMCT8 (Slc16a2) gene defectSLC17A5 gene defect

Hypomyelination

Yes

No

Cystic changes

MLC1RNASET2 gene defect