Klinische FragestellungNeuropathie, CMT/HMSN; Differentialdiagnose

NGS +

[[Sanger]]

Hereditäre motorische und sensorische Neuropathien (HMSN) oder Charcot-Marie-Tooth-(CMT) Erkrankungen und verwandte Neuropathien sind eine Gruppe von klinisch und genetisch heterogenen Leiden, die primär das periphere Nervensystem mit sekundärem Muskelschwund und Schwäche betreffen. CMT ist die häufigste vererbte neuromuskuläre Störung, und diese Patienten können sich mit vielen Symptomen präsentieren, wobei in allen Altersgruppen üblicherweise motorische Anzeichen gegenüber sensorischen Symptomen überwiegen. CMT kann im Säuglingsalter beginnen, in der Adoleszenz oder lebenslang mit milden Symptomen auftreten - selbst asymptomatische Verwandte können in einigen Familien nachgewiesen werden. Die motorischen Nervenleit-Geschwindigkeiten (NCV) unterscheiden zwei Haupttypen: CMT1 (demyelinisierend; NCV<35m/sec) und CMT2 (axonal; NCV>45m/sec). CMT1 macht etwa 2/3 aller CMT-Fälle aus. Die CMT-Neuropathie kann entweder autosomal dominant, rezessiv oder X-chromosomal (CMTX-Formen) vererbt werden und tritt häufig als sporadische Neuropathie auf. Bislang wurden über 60 verschiedene genetische Loci mit CMT1-4 und CMTdi (dominanter intermediärer Typ; NCV 35-45m/sec) in Verbindung gebracht. Fast alle der relevanten Gene sind identifiziert. Diese Gene kodieren für Proteine, die an der Myelinisierung, der Schwann-Zell-Differenzierung, dem axonalen Transport, dem endozytären Recycling, der mitochondrialen Funktion, der Protein-Translation, der Signaltransduktion, der Reparatur von Einzelstrang-DNA-Brüchen und anderen Prozessen beteiligt sind. Die bisher berichteten DNA-Diagnoseausbeuten für alle CMT-Formen unterscheiden sich erheblich von >20% bis >60%, wahrscheinlich in Abhängigkeit vom Grad der klinischen Aufarbeitung. Negative molekulargenetische Ergebnisse schließen die klinische Diagnose keinesfalls aus.

Referenz: https://www.ncbi.nlm.nih.gov/books/NBK1358/

• Alias: Axonal + demyelinating neuropathies
• Alias: CMT1, CMT2, CMT3, CMTX; HMSNI, HMSNII, HMSNIII ...
• Alias: Polyneuropathie
• Allelic: Alpha-aminoadipic + alpha-ketoadipic aciduria (DHTKD1)
• Allelic: Amyotrophic lateral sclerosis 11 (FIG4)
• Allelic: Amyotrophic lateral sclerosis 16, juvenile (SIGMAR1)
• Allelic: Amyotrophic lateral sclerosis 4, juvenile (SETX)
• Allelic: Amyotrophic lateral sclerosis 5, juvenile (SPG11)
• Allelic: Amyotrophic lateral sclerosis, susceptibility to (DCTN1)
• Allelic: Amyotrophic lateral sclerosis, susceptibility to (NEFH)
• Allelic: Amyotrophic lateral sclerosis, susceptibility to, 25 (KIF5A)
• Allelic: Arts syndrome (PRPS1)
• Allelic: Ataxia-oculomotor apraxia 4 (PNKP)
• Allelic: Avascular necrosis of femoral head, primary, 2 (TRPV4)
• Allelic: Brachyolmia type 3 (TRPV4)
• Allelic: Cardiomyopathy, dilated, 1A (LMNA)
• Allelic: Cardiomyopathy, dilated, 1HH (BAG3)
• Allelic: Centronuclear myopathy 1 (DNM2)
• Allelic: Cerebellar ataxia, deafness, and narcolepsy, AD (DNMT1)
• Allelic: Cortical dysplasia, complex, with other brain malformations 1 (TUBB3)
• Allelic: Cutis laxa, AD 2 (FBLN5)
• Allelic: Cutis laxa, AR, type IA (FBLN5)
• Allelic: Deafness, AR 89 (KARS1)
• Allelic: Deafness, XL 1 (PRPS1)
• Allelic: Deafness, XL 5 (AIFM1)
• Allelic: Deafness, congenital + adult-onset progressive leukoencephalopathy (KARS1)
• Allelic: Developmental + epileptic encephalopathy 29 (AARS1)
• Allelic: Digital arthropathy-brachydactyly, familial (TRPV4)
• Allelic: Dystransthyretinemic hyperthyroxinemia (TTR)
• Allelic: Emery-Dreifuss muscular dystrophy 2, AD (LMNA)
• Allelic: Emery-Dreifuss muscular dystrophy 3, AR (LMNA)
• Allelic: Encephalopathy, progressive, +/- lipodystrophy (BSCL2)
• Allelic: Epidermolysis bullosa simplex 3, localized/generalized intermediate, bp230 deficiency (DST)
• Allelic: Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 (CHCHD10)
• Allelic: Frontotemporal dementia and/or amyotrophic lateral sclerosis 6 (VCP)
• Allelic: Glomerulosclerosis, focal segmental, 5 (INF2)
• Allelic: Gout, PRPS-related (PRPS1)
• Allelic: Heart-hand syndrome, Slovenian type (LMNA)
• Allelic: Hemolytic anemia due to hexokinase deficiency (HK1)
• Allelic: Hutchinson-Gilford progeria (LMNA)
• Allelic: Hypomagnesemia, seizures + mental retardation 2 (ATP1A1)
• Allelic: Inclusion body myopathy with early-onset Paget disease + frontotemporal dementia 1 (VCP)
• Allelic: Infantile-onset multisystem neurologic, endocrine + pancreatic disease 2 (YARS1)
• Allelic: Interstitial lung + liver disease (MARS1)
• Allelic: Lethal congenital contracture syndrome 5 (DNM2)
• Allelic: Leukoencephalopathy, progressive, infantile-onset, with/-out deafness (KARS1)
• Allelic: Lipodystrophy, congenital generalized, type 2 (BSCL2)
• Allelic: Lipodystrophy, familial partial, type 2 (LMNA)
• Allelic: Macular degeneration, age-related, 3 (FBLN5)
• Allelic: Malouf syndrome (LMNA)
• Allelic: Mandibuloacral dysplasia (LMNA)
• Allelic: Medulloblastoma (ELP1)
• Allelic: Menkes disease (ATP7A)
• Allelic: Mental retardation, AD 13 (DYNC1H1)
• Allelic: Metatropic dysplasia (TRPV4)
• Allelic: Microcephaly, seizures, developmental delay (PNKP)
• Allelic: Mitochondrial DNA depletion syndrome 6 [hepatocerebral type] (MPV17)
• Allelic: Mitochondrial complex IV deficiency, nuclear type 1 (SURF1)
• Allelic: Mononeuropathy of the median nerve, mild (SH3TC2)
• Allelic: Mucopolysaccharidosis type IIIB [Sanfilippo B] (NAGLU)
• Allelic: Muscular dystrophy, congenital (LMNA)
• Allelic: Myoclonus, intractable, neonatal (KIF5A)
• Allelic: Myopathy, isolated mitochondrial, AD (CHCHD10)
• Allelic: Myopathy, myofibrillar, 6 (BAG3)
• Allelic: Myopia 6 (SCO2)
• Allelic: NESCAV syndrome (KIF1A)
• Allelic: Neuroblastoma, susceptibility to, 1 (KIF1B)
• Allelic: Neurodevelopmental disorder with visual defects + brain anomalies (HK1)
• Allelic: Occipital horn syndrome (ATP7A)
• Allelic: Parastremmatic dwarfism (TRPV4)
• Allelic: Perry syndrome (DCTN1)
• Allelic: Pheochromocytoma (KIF1B)
• Allelic: Phosphoribosylpyrophosphate synthetase superactivity (PRPS1)
• Allelic: Polymicrogyria, bilateral temporooccipital (FIG4)
• Allelic: Restrictive dermopathy, lethal (LMNA)
• Allelic: Retinitis pigmentosa 79 (HK1)
• Allelic: Roussy-Levy syndrome (MPZ, PMP22)
• Allelic: Scapuloperoneal spinal muscular atrophy (TRPV4)
• Allelic: Silver spastic paraplegia syndrome (BSCL2)
• Allelic: Sodium serum level QTL 1 (TRPV4)
• Allelic: Spastic paraplegia 10, AD (KIF5A)
• Allelic: Spastic paraplegia 11, AR (SPG11)
• Allelic: Spastic paraplegia 30, AD (KIF1A)
• Allelic: Spastic paraplegia 30, AR (KIF1A)
• Allelic: Spastic paraplegia 57, AR (TFG)
• Allelic: Spinal muscular atrophy, distal, AR, 4 (PLEKHG5)
• Allelic: Spinal muscular atrophy, distal, AR, 5 (DNAJB2)
• Allelic: Spinal muscular atrophy, infantile, James type (GARS1)
• Allelic: Spinal muscular atrophy, lower extremity-predominant 1, AD (DYNC1H1)
• Allelic: Spinocerebellar ataxia 43 (MME)
• Allelic: Spondyloepimetaphyseal dysplasia, Maroteaux type (TRPV4)
• Allelic: Spondyloepimetaphyseal dysplasia, XL, with hypomyelinating leukodystrophy (AIFM1)
• Allelic: Spondylometaphyseal dysplasia, Kozlowski type (TRPV4)
• Allelic: Usher syndrome type 3B (HARS1)
• Allelic: Yunis-Varon syndrome (FIG4)
• Amyloidosis, hereditary, transthyretin-related (TTR)
• Basel-Vanagait-Smirin-Yosef syndrome (MED25)
• Carpal tunnel syndrome, familial (TTR)
• Charcot-Marie-Tooth disease, XLD, 6 (PDK3)
• Charcot-Marie-Tooth disease, XLR, 5 (PRPS1)
• Charcot-Marie-Tooth disease, axonal type 2A2A (MFN2)
• Charcot-Marie-Tooth disease, axonal type 2A2B (MFN2)
• Charcot-Marie-Tooth disease, axonal type 2CC (NEFH)
• Charcot-Marie-Tooth disease, axonal type 2DD (ATP1A1)
• Charcot-Marie-Tooth disease, axonal type 2EE (MPV17)
• Charcot-Marie-Tooth disease, axonal type 2F (HSPB1)
• Charcot-Marie-Tooth disease, axonal type 2K (GDAP1)
• Charcot-Marie-Tooth disease, axonal type 2L (HSPB8)
• Charcot-Marie-Tooth disease, axonal type 2M (DNM2)
• Charcot-Marie-Tooth disease, axonal type 2N (AARS1)
• Charcot-Marie-Tooth disease, axonal type 2O (DYNC1H1)
• Charcot-Marie-Tooth disease, axonal type 2P (LRSAM1)
• Charcot-Marie-Tooth disease, axonal type 2Q (DHTKD1)
• Charcot-Marie-Tooth disease, axonal type 2R (TRIM2)
• Charcot-Marie-Tooth disease, axonal type 2S (IGHMBP2)
• Charcot-Marie-Tooth disease, axonal type 2T (MME)
• Charcot-Marie-Tooth disease, axonal type 2U (MARS)
• Charcot-Marie-Tooth disease, axonal type 2V (NAGLU)
• Charcot-Marie-Tooth disease, axonal type 2W (HARS1)
• Charcot-Marie-Tooth disease, axonal type 2X (SPG11)
• Charcot-Marie-Tooth disease, axonal type 2Z (MORC2)
• Charcot-Marie-Tooth disease, axonal with vocal cord paresis (GDAP1)
• Charcot-Marie-Tooth disease, axonal, type 2FF (CADM3)
• Charcot-Marie-Tooth disease, demyelinating type 1G (PMP2)
• Charcot-Marie-Tooth disease, demyelinating, type 1H (FBLN5)
• Charcot-Marie-Tooth disease, dominant intermediate B (DNM2)
• Charcot-Marie-Tooth disease, dominant intermediate C (YARS1)
• Charcot-Marie-Tooth disease, dominant intermediate D (MPZ)
• Charcot-Marie-Tooth disease, dominant intermediate E (INF2)
• Charcot-Marie-Tooth disease, dominant intermediate F (GNB4)
• Charcot-Marie-Tooth disease, dominant intermediate G (NEFL)
• Charcot-Marie-Tooth disease, recessive intermediate A (GDAP1)
• Charcot-Marie-Tooth disease, recessive intermediate B (KARS1)
• Charcot-Marie-Tooth disease, recessive intermediate C (PLEKHG5)
• Charcot-Marie-Tooth disease, recessive intermediate D (COX6A1)
• Charcot-Marie-Tooth disease, type 1A (PMP22)
• Charcot-Marie-Tooth disease, type 1B (MPZ)
• Charcot-Marie-Tooth disease, type 1C (LITAF)
• Charcot-Marie-Tooth disease, type 1D (EGR2)
• Charcot-Marie-Tooth disease, type 1E (PMP22)
• Charcot-Marie-Tooth disease, type 1F (NEFL)
• Charcot-Marie-Tooth disease, type 2A1 (KIF1B)
• Charcot-Marie-Tooth disease, type 2B (RAB7A)
• Charcot-Marie-Tooth disease, type 2B1 (LMNA)
• Charcot-Marie-Tooth disease, type 2B2 (PNKP)
• Charcot-Marie-Tooth disease, type 2D (GARS1)
• Charcot-Marie-Tooth disease, type 2E (NEFL)
• Charcot-Marie-Tooth disease, type 2I (MPZ)
• Charcot-Marie-Tooth disease, type 2J (MPZ)
• Charcot-Marie-Tooth disease, type 2R (TRIM2)
• Charcot-Marie-Tooth disease, type 2Y (VCP)
• Charcot-Marie-Tooth disease, type 4A (GDAP1)
• Charcot-Marie-Tooth disease, type 4B1 (MTMR2)
• Charcot-Marie-Tooth disease, type 4B2 (SBF2)
• Charcot-Marie-Tooth disease, type 4B3 (SBF1)
• Charcot-Marie-Tooth disease, type 4C (SH3TC2)
• Charcot-Marie-Tooth disease, type 4D (NDRG1)
• Charcot-Marie-Tooth disease, type 4F (PRX)
• Charcot-Marie-Tooth disease, type 4H (FGD4)
• Charcot-Marie-Tooth disease, type 4J (FIG4)
• Charcot-Marie-Tooth disease, type 4K (SURF1)
• Charcot-Marie-Tooth neuropathy, XLD, 1 (GJB1)
• Combined oxidative phosphorylation deficiency 6 (AIFM1)
• Congenital cataracts, facial dysmorphism + neuropathy (CTDP1)
• Cowchock syndrome (AIFM1)
• Dejerine-Sottas disease (EGR2, MPZ, PMP22, PRX)
• Developmental delay, impaired growth, dysmorphic facies + axonal neuropathy (MORC2)
• Dysautonomia, familial (ELP1)
• Fibrosis of extraocular muscles, congenital, 3A (TUBB3)
• Giant axonal neuropathy-1, AR (GAN)
• Giant axonal neuropathy-2, AD (DCAF8)
• Hereditary Neuropathies [panelapp] (KIF5A)
• Hereditary motor + sensory neuropathy VIA (MFN2)
• Hereditary motor + sensory neuropathy, Okinawa type (TFG)
• Hereditary motor + sensory neuropathy, type IIc (TRPV4)
• Hypomyelinating neuropathy, congenital, 1 (EGR2)
• Hypomyelinating neuropathy, congenital, 2 (MPZ)
• Hypomyelinating neuropathy, congenital, 3 (CNTNAP1)
• Infantile-onset multisystem neurologic, endocrine + pancreatic disease (PTRH2)
• Lethal congenital contracture syndrome 7 (CNTNAP1)
• Mitochondrial complex IV deficiency, nuclear type 2 (SCO2)
• Nephrotic syndrome, type 14 (SGPL1)
• Neurodevelopmental disorder with microcephaly, ataxia, seizures (SARS1)
• Neuromyotonia and axonal neuropathy, AR (HINT1)
• Neuronopathy, distal hereditary motor, type IIA (HSPB8)
• Neuronopathy, distal hereditary motor, type IIB (HSPB1)
• Neuronopathy, distal hereditary motor, type IIC (HSPB3)
• Neuronopathy, distal hereditary motor, type IX (WARS1)
• Neuronopathy, distal hereditary motor, type VA (GARS1)
• Neuronopathy, distal hereditary motor, type VI (IGHMBP2)
• Neuronopathy, distal hereditary motor, type VIIB (DCTN1)
• Neuronopathy, distal hereditary motor, type VIII (TRPV4)
• Neuropathy, axonal [GeneReviews] (DGAT2)
• Neuropathy, distal hereditary motor, type VC (BSCL2)
• Neuropathy, hereditary motor + myopathic features (VWA1)
• Neuropathy, hereditary motor + sensory, Russe type (HK1)
• Neuropathy, hereditary motor + sensory, type VIB (SLC25A46)
• Neuropathy, hereditary sensory + autonomic, type IA (SPTLC1)
• Neuropathy, hereditary sensory + autonomic, type V (NGF)
• Neuropathy, hereditary sensory + autonomic, type VI (DST)
• Neuropathy, hereditary sensory + autonomic, type VIII (PRDM12)
• Neuropathy, hereditary sensory, type IE (DNMT1)
• Neuropathy, hereditary sensory, type IIC (KIF1A)
• Neuropathy, hereditary, +/- age-related macular degeneration (FBLN5)
• Neuropathy, inflammatory demyelinating (PMP22)
• Neuropathy, intermediate [GeneReviews] (DRP2)
• Neuropathy, recurrent, with pressure palsies (PMP22)
• Peripheral neuropathy, AR, +/- impaired intellectual development (MCM3AP)
• Polyneuropathy, hearing loss, ataxia, retinitis pigmentosa, + cataract (ABHD12)
• Pontocerebellar hypoplasia, type 1E (SLC25A46)
• Slowed nerve conduction velocity, AD (ARHGEF10)
• Sorbitol dehydrogenase deficiency with peripheral neuropathy (SORD)
• Spinal muscular atrophy, Jokela type (CHCHD10)
• Spinal muscular atrophy, distal, AR, 2 (SIGMAR1)
• Spinal muscular atrophy, distal, XL (ATP7A)
• Spinocerebellar ataxia, AR, with axonal neuropathy 2 (SETX)
• Spinocerebellar ataxia, AR, with axonal neuropathy 3 (COA7)
• Vocal cord paresis [GeneReviews: as the first manifestation of CMT] (DCTN2)