IllnessLeigh syndrome, differential diagnosis

NGS +

[[Sanger]]

Leigh syndrome (LS) is a severe neurological disorder that usually occurs in the first year of life. The disorder is characterized by progressive psychomotor regression and usually leads to death within 2-3 years, often due to respiratory failure. In a small number of patients, symptoms do not appear until adulthood or worsen more slowly. Initial signs of LS are usually vomiting, diarrhea, dysphagia and later failure to thrive. Severe muscle and movement problems are also common. Affected individuals may develop hypotonia, dystonia, ataxia and peripheral neuropathy. Many affected individuals have ophthalmoparesis, nystagmus or optic atrophy. Severe respiratory problems are common and can lead to acute respiratory failure. Some patients develop hypertrophic cardiomyopathy and lactic acidosis. These symptoms are caused in part by lesions in the brain (basal ganglia, cerebellum, brainstem) due to demyelination. LS can be caused by variants in any of ~100 different nuclear genes, ~20% of LS cases have a variant in mtDNA. Most genes associated with LS are involved in the process of energy generation in mitochondria. One of the most frequently altered nuclear genes in LS is SURF1, the inheritance pattern is usually autosomal recessive. Since the diagnostic yield via molecular genetics barely exceeds 60%, a negative DNA test result does not refute the clinical diagnosis.

Referenz: https://www.ncbi.nlm.nih.gov/books/NBK320989/

https://www.ncbi.nlm.nih.gov/books/NBK1173/

• Alias: Leigh syndrome due to mitochondrial complex I-V deficiency
• Allelic: Bjornstad syndrome (BCS1L)
• Allelic: Cardioencephalomyopathy, fatal infantile, due to cytochrome c oxidase deficiency 2 (COX15)
• Allelic: Cardiomyopathy, dilated, 1GG (SDHA)
• Allelic: Cataract 38, AR (AGK)
• Allelic: Charcot-Marie-Tooth disease, axonal, type 2EE (MPV14)
• Allelic: Charcot-Marie-Tooth disease, axonal, types 2A2A + 2A2B (MFN2)
• Allelic: Charcot-Marie-Tooth disease, type 4K (SURF1)
• Allelic: Deafness, AR 70 (PNPT1)
• Allelic: Deafness, AR 94 (NARS2)
• Allelic: Deafness, AR 94 (NDUFA4)
• Allelic: Deafness, mitochondrial, modifier of (TRMU)
• Allelic: Fanconi renotubular syndrome 5 (NDUFAF2, NDUFAF6)
• Allelic: GRACILE syndrome (BCS1L)
• Allelic: Glaucoma, normal tension, susceptibility to (OPA1)
• Allelic: Hereditary motor + sensory neuropathy VIA (MFN2)
• Allelic: Leukoencephalopathy, progressive, with ovarian failure (AARS2)
• Allelic: Liver failure, transient infantile (TRMU)
• Allelic: Microcephaly, Amish type (SLC25A19)
• Allelic: Multiple system atrophy, susceptibility to (COQ2)
• Allelic: Myopia 6 (SCO2)
• Allelic: Neuropathy, hereditary motor + sensory, type VIB (SLC25A46)
• Allelic: Optic atrophy 1 (OPA1)
• Allelic: Optic atrophy 12 (AFG3L2)
• Allelic: Optic atrophy plus syndrome (OPA1)
• Allelic: Paragangliomas 5 (SDHA)
• Allelic: Perrault syndrome 5 (TWNK)
• Allelic: Portal hypertension, noncirrhotic, 1 (DGUOK)
• Allelic: Seckel syndrome 8 (DNA2)
• Allelic: Spastic ataxia 5, AR (AFG3L2)
• Allelic: Spinocerebellar ataxia 28 (AFG3L2)
• 3-hydroxyisobutryl-CoA hydrolase deficiency (HIBCH)
• 3-methylglutaconic aciduria with deafness, encephalopathy + Leigh-like syndrome (SERAC1)
• 3-methylglutaconic aciduria, type VII, with cataracts, neurologic involvement + neutropenia (CLPB)
• Ataxia, early-onset, with oculomotor apraxia and hypoalbuminemia (APTX)
• Behr syndrome (OPA1)
• Biotinidase deficiency (BTD)
• Cataracts/growth hormone deficiency/sensory neuropathy/sensorineur. hear loss/skel. dyspl. (IARS2)
• Coenzyme Q10 deficiency, primary, 1 (COQ2)
• Coenzyme Q10 deficiency, primary, 2 (PDSS1)
• Coenzyme Q10 deficiency, primary, 3 (PDSS2)
• Coenzyme Q10 deficiency, primary, 4 (COQ8A)
• Coenzyme Q10 deficiency, primary, 5 (COQ9)
• Coenzyme Q10 deficiency, primary, 6 (COQ6)
• Coenzyme Q10 deficiency, primary, 7 (COQ4)
• Combined oxidative phosphorylation deficiency 1 (GFM1)
• Combined oxidative phosphorylation deficiency 12 (EARS2)
• Combined oxidative phosphorylation deficiency 13 (PNPT1)
• Combined oxidative phosphorylation deficiency 14 (FARS2)
• Combined oxidative phosphorylation deficiency 15 (MTFMT)
• Combined oxidative phosphorylation deficiency 23 (GTPBT3)
• Combined oxidative phosphorylation deficiency 24 (NARS2)
• Combined oxidative phosphorylation deficiency 3 (TSFM)
• Combined oxidative phosphorylation deficiency 32 (MRPS34)
• Combined oxidative phosphorylation deficiency 39 (GFM2)
• Combined oxidative phosphorylation deficiency 51 (PTCD3)
• Combined oxidative phosphorylation deficiency 7 (MTRFR)
• Combined oxidative phosphorylation deficiency 8 (AARS2)
• Congenital disorder of glycosylation, type IIn (SLC39A8)
• Dihydrolipoamide dehydrogenase deficiency (DLD)
• Encephalopathy due to defective mitochondrial + peroxisomal fission 2 (MFF)
• Ethylmalonic encephalopathy (ETHE1)
• GABA-transaminase deficiency (ABAT)
• Glutaric acidemia IIC (ETFDH)
• Hyperglycinemia, lactic acidosis + seizures (LIAS)
• Lacticacidemia due to PDX1 deficiency (PDHX)
• Leigh syndrome (BCS1L, SDHA)
• Leigh syndrome due to cytochrome c oxidase deficiency (COX15)
• Leigh syndrome due to mitochondrial COX4 deficiency (COX10)
• Leigh syndrome, due to COX IV deficiency (SURF1)
• Lipoyltransferase 1 deficiency (LIPT1)
• Mitochondrial DNA depletion syndrome 1, MNGIE type (TYMP)
• Mitochondrial DNA depletion syndrome 11 (MGME1)
• Mitochondrial DNA depletion syndrome 12A, cardiomyopathic type, AD (SLC25A4)
• Mitochondrial DNA depletion syndrome 12B, cardiomyopathic type) AR (SLC25A4)
• Mitochondrial DNA depletion syndrome 13, encephalomyopathic type (FBXL4)
• Mitochondrial DNA depletion syndrome 14, encephalocardiomyopathic type (OPA1)
• Mitochondrial DNA depletion syndrome 15, hepatocerebral type (TFAM)
• Mitochondrial DNA depletion syndrome 16, hepatic type (POLG2)
• Mitochondrial DNA depletion syndrome 16B, neuroophthalmic type (POLG2)
• Mitochondrial DNA depletion syndrome 18 (SLC25A21)
• Mitochondrial DNA depletion syndrome 2, myopathic type (TK2)
• Mitochondrial DNA depletion syndrome 3, hepatocerebral type (DGUOK)
• Mitochondrial DNA depletion syndrome 4A, Alpers type + 4B, MNGIE type (POLG)
• Mitochondrial DNA depletion syndrome 5, encephalomyopathic +/- methylmalonic aciduria (SUCLA2)
• Mitochondrial DNA depletion syndrome 6, hepatocerebral type (MPV14)
• 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 DNA depletion syndrome 9, encephalomyopathic type + methylmalonic aciduria (SUCLG1)
• Mitochondrial complex I deficiency, nuclear type 1 (NDUFS4)
• Mitochondrial complex I deficiency, nuclear type 13 (NDUFA2)
• Mitochondrial complex I deficiency, nuclear type 15 (NDUFAF4)
• Mitochondrial complex I deficiency, nuclear type 16 (NDUFAF5)
• Mitochondrial complex I deficiency, nuclear type 17 (NDUFAF2, NDUFAF6)
• Mitochondrial complex I deficiency, nuclear type 19 (FOXRED1)
• Mitochondrial complex I deficiency, nuclear type 2 (NDUFS8)
• Mitochondrial complex I deficiency, nuclear type 20 (ACAD9)
• Mitochondrial complex I deficiency, nuclear type 21 (NUBPL)
• Mitochondrial complex I deficiency, nuclear type 22 (NDUFA10)
• Mitochondrial complex I deficiency, nuclear type 23 (NDUFA12)
• Mitochondrial complex I deficiency, nuclear type 26 (NDUFA9)
• Mitochondrial complex I deficiency, nuclear type 27 (MTFMT)
• Mitochondrial complex I deficiency, nuclear type 3 (NDUFS7)
• Mitochondrial complex I deficiency, nuclear type 31 (TIMMDC1)
• Mitochondrial complex I deficiency, nuclear type 34 (NDUFAF8)
• 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 I deficiency, nuclear type 7 (NDUFV2)
• Mitochondrial complex I deficiency, nuclear type 8 (NDUFS3)
• Mitochondrial complex II deficiency, nuclear type 2 (SDHAF1)
• Mitochondrial complex III deficiency, nuclear type 1 (BCS1L)
• Mitochondrial complex III deficiency, nuclear type 2 (TTC19)
• Mitochondrial complex III deficiency, nuclear type 4 (UQCRQ)
• Mitochondrial complex IV deficiency (COX10)
• Mitochondrial complex IV deficiency, nuclear type 12 (PET100)
• Mitochondrial complex IV deficiency, nuclear type 15 (COX8A)
• Mitochondrial complex IV deficiency, nuclear type 19 (PET117)
• Mitochondrial complex IV deficiency, nuclear type 2 (SCO2)
• Mitochondrial complex IV deficiency, nuclear type 21 (NDUFA4)
• Mitochondrial complex IV deficiency, nuclear type 5, French-Canadian (LRPPRC)
• Mitochondrial complex IV deficiency, nuclear type 8 (TACO1)
• Mitochondrial recessive ataxia syndrome; includes SANDO + SCAE (POLG)
• Mitochondrial respiratory chain complex II deficiency (SDHA)
• Mitochondrial short-chain enoyl-CoA hydratase 1 deficiency (ECHS1)
• Myopathy, mitochondrial progressive, with congenital cataract + developmental delay (GFER)
• Pontocerebellar hypoplasia, type 1E (SLV25A46)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD (TWNK)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AD 2 (SLC25A4)
• 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, AD 6 (DNA2)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AR 2 (RNASEH1)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AR 3 (TK2)
• Progressive external ophthalmoplegia with mitochondrial DNA deletions, AR 4 (DGUOK)
• Progressive external ophthalmoplegia, AD 1 (POLG)
• Progressive external ophthalmoplegia, AR 1 (POLG)
• Pyruvate dehydrogenase E1-beta deficiency (PDHB)
• Pyruvate dehydrogenase E2 deficiency (DLAT)
• Sengers syndrome (AGK)
• Spastic paraplegia 55, AR (MTRFR)
• Spastic paraplegia 7, AR (SPG7)
• Spastic paraplegia 77, AR (FARS2)
• Spinocerebellar ataxia, AR 10 (ANO10)
• Sulfide:quinone oxidoreductase deficiency (SQOR)
• Thiamine metabolism dysfunction syndrome 2, biotin-/thiamine-responsive encephalopathy 2 (SLC19A3)
• Thiamine metabolism dysfunction syndrome 4, progressive polyneuropathy type (SLC25A19)
• Thiamine metabolism dysfunction syndrome 5, episodic encephalopathy type (TPK1)