IllnessLeukodystrophy, early onset; differential diagnosis

NGS +

Leukodystrophies are a group of rare, genetic metabolic diseases that affect the brain, spinal cord, and often peripheral nerves. Each of the many forms of early-onset leukodystrophy is caused by a specific gene mutation that leads to impaired development or destruction of the brain's myelin sheath. Each type of leukodystrophy affects different portions of the myelin sheath, resulting in a long list of neurological problems. Symptoms of some types of leukodystrophy begin shortly after birth, while others develop later in childhood (or even in adulthood). These symptoms vary by type and can be difficult to diagnose in the early stages of the disease. The most common symptom is a gradual deterioration of function in an infant or child who previously appeared healthy. There may be progressive loss of muscle tone, gait, balance, speech, vision, hearing, behavior, developmental delays and learning difficulties, breathing problems and/or seizures. Many leukodystrophies are progressive diseases that worsen over time. However, some inherited leukoencephalopathies have stable white matter changes. The broad spectrum of early forms of leukodystrophy includes e.g. Aicardi-Goutieres syndrome (encephalopathy with basal ganglia calcification), Alexander disease (neonatal and infantile forms), cerebrotendinous xanthomatosis, the classic form of Fabry disease (alpha-galactosidase A deficiency), Krabbe disease (globoid cell leukodystrophy), metachromatic leukodystrophy (arylsulfatase A deficiency), Pelizaeus-Merzbacher disease (PLP1 disorder), the cerebral form of childhood X-linked adrenoleukodystrophy and the numerous Zellweger syndrome spectrum disorders (e.g. neonatal adrenoleukodystrophy as well as infantile Refsum disease). In the early-onset leukodystrophies, all monogenic inheritance patterns are observed. The diagnostic yield is about 70%, so a negative DNA test result does not exclude the clinical diagnosis.

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• Alias: Leukencephalopathie
• Alias: Leukencephalopathy
• Alias: Leukodystrophie
• Alias: Leukodystrophy
• Alias: Leukoencephalopathy
• Alias: Leukoenzephalopathie
• Allelic: 5-fluorouracil toxicity (DPYD)
• Allelic: Adrenomyeloneuropathy, adult (ABCD1)
• Allelic: Angiopathy, hereditary, with nephropathy, aneurysms + muscle cramps (COL4A1)
• Allelic: Bjornstad syndrome (BCS1L)
• Allelic: Chromosome 5q14.3 deletion syndrome (MEF2C)
• Allelic: Combined SAP deficiency (PSAP)
• Allelic: Dermatofibrosarcoma protuberans (PDGFB)
• Allelic: Dyschromatosis symmetrica hereditaria (ADAR)
• Allelic: Gastrointestinal stromal tumor (SDHB)
• Allelic: Gaucher disease, atypical (PSAP)
• Allelic: Kosaki overgrowth syndrome (PDGFRB)
• Allelic: Krabbe disease, atypical (PSAP)
• Allelic: Lung cancer, susceptibility to (ERCC6)
• Allelic: Lymphatic malformation 3 (GJC2)
• Allelic: Macular degeneration, age-related, susceptibility to, 5 (ERCC6)
• Allelic: Meningioma, SIS-related (PDGFB)
• Allelic: Mitchell syndrome (ABCD1)
• Allelic: Myeloproliferative disorder with eosinophilia (PDGFRB)
• Allelic: Myofibromatosis, infantile, 1 (PDGFRB)
• Allelic: Myopia 6 (SCO2)
• Allelic: Ovarioleukodystrophy (EIF2B2, EIF2B4, EIF2B5)
• Allelic: Paraganglioma + gastric stromal sarcoma (SDHB)
• Allelic: Paragangliomas 4 (SDHB)
• Allelic: Perrault syndrome 1 (HSD17B4)
• Allelic: Perrault syndrome 5 (TWNK)
• Allelic: Pheochromocytoma (SDHB)
• Allelic: Portal hypertension, noncirrhotic, 1 (DGUOK)
• Allelic: Premature ovarian failure 11 (ERCC6)
• Allelic: Retinal arteries, tortuosity of (COL4A1)
• Allelic: Spastic paraplegia 2, XL (PLP1)
• Allelic: Spastic paraplegia 44, AR (GJC2)
• Allelic: Systemic lupus erythematosus, susceptibility to (TREX1)
• Allelic: UV-sensitive syndrome 1 (ERCC6)
• Allelic: UV-sensitive syndrome 2 (ERCC8)
• Adrenoleukodystrophy (ABCD1)
• Aicardi-Goutieres syndrome 1, AD + AR (TREX1)
• Aicardi-Goutieres syndrome 2 (RNASE2B)
• Aicardi-Goutieres syndrome 3 (RNASE2C)
• Aicardi-Goutieres syndrome 4 (RNASE2H)
• Aicardi-Goutieres syndrome 5 (SMAHD1)
• Aicardi-Goutieres syndrome 6 (ADAR)
• Aicardi-Goutieres syndrome 7 (IFIH1)
• Aicardi-Goutieres syndrome 8 (LSM11)
• Alexander disease (GFAP)
• Allan-Herndon-Dudley syndrome (SLC16A2)
• Basal ganglia calcification, idiopathic, 1 (SLC20A2)
• Basal ganglia calcification, idiopathic, 4 (PDGFRB)
• Basal ganglia calcification, idiopathic, 5 (PDGFB)
• Basal ganglia calcification, idiopathic, 6 (XPR1)
• Brain abnormalities, neurodegeneration + dysosteosclerosis (CSF1R)
• Brain small vessel disease with/-out ocular anomalies (COL4A1)
• Canavan disease (ASPA)
• Cerebrooculofacioskeletal syndrome 1 (ERCC6)
• Cerebrooculofacioskeletal syndrome 2 (ERCC2)
• Cerebrooculofacioskeletal syndrome 3 (ERCC5)
• Cerebrooculofacioskeletal syndrome 4 (ERCC1)
• Cerebroretinal microangiopathy with calcifications + cysts (CTC1)
• Cerebrotendinous xanthomatosis (CYP27A1)
• Charcot-Marie-Tooth disease, type 4K (SURF1)
• Charcot-Marie-Tooth neuropathy, XLD, 1 (GJB1)
• Chilblain lupus (TREX1)
• Chilblain lupus 2 (SAMHD1)
• Cockayne syndrome, type A (ERRC8)
• Cockayne syndrome, type B (ERCC6)
• Coenzyme Q10 deficiency, primary, 1 (COQ2)
• Coenzyme Q10 deficiency, primary, 4 (COQ8A)
• Combined SAP deficiency (PSAP)
• Combined oxidative phosphorylation deficiency 1 (GFM1)
• Combined oxidative phosphorylation deficiency 12 (EARS2)
• Combined oxidative phosphorylation deficiency 15 (MTFMT)
• Combined oxidative phosphorylation deficiency 8 (AARS2)
• Congenital disorder of glycosylation, type IIt (GALNT2)
• D-2-hydroxyglutaric aciduria (D2HGDH)
• D-bifunctional protein deficiency (HSD17B4)
• De Sanctis-Cacchione syndrome (ERCC6)
• Deafness, dystonia + cerebral hypomyelination (BCAP31)
• Developmental + epileptic encephalopathy 39 (SLC25A12)
• Dihydropyrimidine dehydrogenase deficiency (DPYD)
• Dystonia 4, torsion, AD (TUBB4A)
• Epilepsy, idiopathic generalized, susceptibility to, 11 (CLCN2)
• Epilepsy, juvenile absence, susceptibility to, 2 (CLCN2)
• Epilepsy, juvenile myoclonic, susceptibility to, 8 (CLCN2)
• Fanconi anemia, complementation group Q (ERCC4)
• Fucosidosis (FUCA1)
• GRACILE syndrome (BCS1L)
• Gaucher disease, atypical (PSAP)
• Glutaric acidemia IIC (ETFDH)
• Glycogen storage disease IV (GBE1)
• Hemorrhage, intracerebral, susceptibility to (COL4A1)
• Hemorrhagic destruction of the brain, subependymal calcification + cataracts (JAM3)
• Hyperaldosteronism, familial, type II (CLCN2)
• Hypomyelination with brainstem and spinal cord involvement + leg spasticity (DARS1)
• Krabbe disease (GALC)
• Krabbe disease, atypical (PSAP)
• L-2-hydroxyglutaric aciduria (L2HGDH)
• L-2-hydroxyglutaric aciduria (LMNB1)
• Leukodystrophy, hypomyelinating, 10 (PYCR2)
• Leukodystrophy, hypomyelinating, 11 (POLR1C)
• Leukodystrophy, hypomyelinating, 16 (TMEM106B)
• Leukodystrophy, hypomyelinating, 17 (AIMP2)
• Leukodystrophy, hypomyelinating, 2 (GJC2)
• Leukodystrophy, hypomyelinating, 3 (AIMP1)
• Leukodystrophy, hypomyelinating, 5 (FAM126A)
• Leukodystrophy, hypomyelinating, 6 (TUBB4A)
• Leukodystrophy, hypomyelinating, 7, with/-out oligodontia +/- hypogonadotropic hypogonadism (POLR3A)
• Leukodystrophy, hypomyelinating, 8, with/-out oligodontia +/- hypogonadotropic hypogonadism (POLR3B)
• Leukodystrophy, hypomyelinating, 9 (RARS1)
• Leukoencephalopathy with ataxia (CLCN2)
• Leukoencephalopathy with brain stem + spinal cord involvement + lactate elevation (DARS2)
• Leukoencephalopathy with dystonia + motor neuropathy (SCP2)
• Leukoencephalopathy with vanishing white matter (EIF2B1-EIF2B5)
• Leukoencephalopathy, cystic, without megalencephaly (RNASET2)
• Leukoencephalopathy, developmental delay + episodic neurologic regression syndrome (EIF2AK2)
• Leukoencephalopathy, diffuse hereditary, with spheroids (CSF1R)
• Leukoencephalopathy, progressive, with ovarian failure (AARS2)
• Lissencephaly 1 (PAFAH1B1)
• Lissencephaly 5 (LAMB1)
• Megalencephalic leukoenceph. + subcortical cysts 2B, remitting, with/-out ment. retard. (HEPACAM)
• Megalencephalic leukoencephalopathy + subcortical cysts (MLC1)
• Megalencephalic leukoencephalopathy with subcortical cysts 2A (HEPACAM)
• Megalencephalic leukoencephalopathy with subcortical cysts 2B, remitting, with/-out MR (HEPACAM)
• Mental retardation, autosomal dominant 45 (CIC)
• Metachromatic leukodystrophy (ARSA)
• Metachromatic leukodystrophy due to SAP-b deficiency (PSAP)
• Microangiopathy + leukoencephalopathy, pontine, AD (COL4A1)
• Mitchell syndrome (ACOX1)
• Mitochondrial AR ataxia syndrome; includes SANDO + SCAE (POLG)
• Mitochondrial DNA depletion syndrome 1, MNGIE type (TYMP)
• Mitochondrial DNA depletion syndrome 12A, cardiomyopathic type; AD (SLC25A4)
• Mitochondrial DNA depletion syndrome 12B, cardiomyopathic type; AR (SLC25A4)
• Mitochondrial DNA depletion syndrome 16, hepatic type (POLG2)
• Mitochondrial DNA depletion syndrome 16B, neuroophthalmic type (POLG2)
• Mitochondrial DNA depletion syndrome 3, hepatocerebral type (DGUOK)
• Mitochondrial DNA depletion syndrome 4A, Alpers type (POLG)
• Mitochondrial DNA depletion syndrome 4B, MNGIE type (POLG)
• Mitochondrial DNA depletion syndrome 5, encephalomyopathic with/-out methylmalonic aciduria (SUCLA)
• Mitochondrial DNA depletion syndrome 7, hepatocerebral type (TWNK)
• Mitochondrial DNA depletion syndrome 8A, encephalomyopathic type with renal tubulopathy (RRM2B)
• Mitochondrial DNA depletion syndrome 8B, MNGIE type (RRM2B)
• Mitochondrial complex I deficiency, nuclear type 1 (NDUFS4)
• Mitochondrial complex I deficiency, nuclear type 11 (NDUFAF1)
• Mitochondrial complex I deficiency, nuclear type 13 (NDUFA2)
• Mitochondrial complex I deficiency, nuclear type 18 (NDUFAF3)
• Mitochondrial complex I deficiency, nuclear type 2 (NDUFS8)
• Mitochondrial complex I deficiency, nuclear type 21 (NUBPL)
• Mitochondrial complex I deficiency, nuclear type 27 (MTFMT)
• Mitochondrial complex I deficiency, nuclear type 3 (NDUFS7)
• Mitochondrial complex I deficiency, nuclear type 4 (NDUFV1)
• Mitochondrial complex I deficiency, nuclear type 5 (NDUFS1)
• Mitochondrial complex I deficiency, nuclear type 6 (NDUFS2)
• Mitochondrial complex II deficiency, nuclear type 2 (SDHAF1)
• Mitochondrial complex II deficiency, nuclear type 4 (SDHB)
• Mitochondrial complex III deficiency, nuclear type 1 (BCS1L)
• Mitochondrial complex III deficiency, nuclear type 8 (LYRM7)
• Mitochondrial complex IV deficiency, nuclear type 1 (SURF1)
• Mitochondrial complex IV deficiency, nuclear type 2 (SCO2)
• Mitochondrial complex IV deficiency, nuclear type 3 (COX10)
• Mitochondrial complex IV deficiency, nuclear type 4 (SCO1)
• Mitochondrial complex IV deficiency, nuclear type 6 (COX15)
• Mitochondrial complex IV deficiency, nuclear type 8 (TACO1)
• Multiple mitochondrial dysfunctions syndrome 3 (IBA57)
• Multiple mitochondrial dysfunctions syndrome 4 (ISCA2)
• Multiple sulfatase deficiency (SUMF)
• Multiple system atrophy, susceptibility to (COQ2)
• Neurodegeneration due to cerebral folate transport deficiency (FOLR1)
• Neurodevelopmental disorder with hypotonia, stereotypic hand movements + impaired language (MEF2C)
• PCWH [periph. demyel. neuropathy, central dysmyel., Waardenburg, Hirschsprung] syndrome (SOX10)
• Parkinson disease 24, AD, susceptibility to (PSAP)
• Pelizaeus-Merzbacher disease (PLP1 syn. PLP)
• Peroxisomal acyl-CoA oxidase deficiency (ABCD1)
• Peroxisomal acyl-CoA oxidase deficiency (ACOX1)
• Pettigrew syndrome (AP1S2)
• Polyglucosan body disease, adult form (GBE1)
• Premature aging syndrome, Penttinen type (PDGFRB)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD 2 (SLC25A4)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD 3 (TWNK)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD 4 (POLG2)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD 5 (RRM2B)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AR 4 (DGUOK)
• Progressive external ophthalmoplegia, AD (POLG)
• Progressive external ophthalmoplegia, AR 1 (POLG)
• Proliferative vasculopathy + hydranencephaly-hydrocephaly syndrome (FLVCR2)
• Pseudo-TORCH syndrome 1 (OCLN)
• Pseudo-TORCH syndrome 2 (USP18)
• Salla disease (SLC17A5)
• Sialic acid storage disorder, infantile (SLC17A5)
• Singleton-Merten syndrome 1 (IFIH1)
• Sjogren-Larsson syndrome (ALDH3A2)
• Spastic ataxia 8, AR, with hypomyelinating leukodystrophy (NKX6-2)
• Spastic paraplegia 44, AR (GJC2)
• Spastic paraplegia 74, AR (IBA57)
• Subcortical laminar heterotopia (PAFAH1B1)
• Treacher Collins syndrome 3 (POLR1C)
• Trichothiodystrophy 1, photosensitive (ERCC2)
• Trichothiodystrophy 2, photosensitive (ERCC3)
• Vasculopathy, retinal, with cerebral leukoencephalopathy + systemic manifestations (TREX1)
• Waardenburg syndrome, type 2E, with/-out neurologic involvement (SOX10)
• Waardenburg syndrome, type 4C (SOX10)
• Wiedemann-Rautenstrauch syndrome (POLR3A)
• XFE progeroid syndrome (ERCC4)
• Xeroderma pigmentosum, group B (ERCC3)
• Xeroderma pigmentosum, group D (ERCC2)
• Xeroderma pigmentosum, group F (ERCC4)
• Xeroderma pigmentosum, group G (ERCC5)
• Xeroderma pigmentosum, group G/Cockayne syndrome (ERCC5)
• Xeroderma pigmentosum, type F/Cockayne syndrome (ERCC4)