Klinische FragestellungSpinale Muskelatrophie Typ 0, I, II, III, IV; Differentialdiagnose

Stufe 1: CNV-Analyse

DNA-Sequenzanalytik auf besonderen Auftrag hin

NGS +

[Sanger]

Infos zur Krankheit

Die Spinale Muskelatrophie (SMA) ist eine der häufigsten autosomal-rezessiv erblichen Erkrankungen in Europa, die bei schwerer Verlaufsform mit einem frühen kindlichen Tod einhergeht. Die Häufigkeit der heterozygoten Anlageträger wird mit 1/40 bis 1/60 für die europäische Bevölkerung angegeben. Auch in Kulturen mit einer hohen Frequenz an Konsanguinität sind autosomal-rezessive Erkrankungen wie SMA weit verbreitet (1). Bei der überwiegenden Mehrheit der betroffenen Kinder ist der Verlust beider SMN1-Genkopien die Erkrankungsursache. Die Eltern tragen dann in der Regel den SMN1-Genkopienverlust auf nur einem Allel. Nach aktuellem Kenntnisstand wird der unterschiedliche Verlauf der SMA Formen I bis III bzw. das unterschiedliche Manifestationsalter wesentlich durch die Anzahl der vorhandenen Kopien des chromosomal benachbarten und nahezu identischen SMN2-Gens beeinflusst. Von diesem Gen wird, im Vergleich zum SMN1-Gen, nur eine geringe Menge Volllängen-Transkript abgelesen (2, 3). - Mehrere gentherapeutische Ansätze sind zwischenzeitlich etabliert oder noch in der klinischen Erprobung. Z.B. das Medikament Nusinersen (SpinrazaTM) erhöht als Antisense-Oligonukleotid die Produktion des SMN Transkripts durch verbessertes Spleißen des SMN2-Gens, kann also nur wirken, wenn ausreichend Genkopien des SMN2-Gens vorliegen (4). Onasemnogene Abeparvovec (ZolgensmaTM) ist eine Adeno-assoziiertes Virus 9 basierte Gentherapie mit der eine Transgen-Kopie des SMN1-Gens eingeschleust wird, die für das SMN-Protein kodiert (5).

Literatur: (1) Shafeghati Y et al. Arch Iranian Med. 7(1): 47 – 52; 2004. (2) Prior, TW et al.; Genet Med. 2011 Jul;13(7):686-94. (3) Prior, TW and Finanger, E; online Gene Reviews http://www.ncbi.nlm.nih.gov/books/NBK1352/. (4) Ottensen. Transl Neurosci. 2017; 8: 1–6. (5) Hoy SM. Onasemnogene Abeparvovec: First Global Approval. Drugs. 2019 Jul;79(11):1255-1262.

ORPHA:83330 Proximal spinal muscular atrophy type 1; ORPHA:83418 SMA type 2; ORPHA:83419 SMA type 3; ORPHA:83420 SMA type 4

ORPHA:83330 Proximal spinal muscular atrophy type 1

Severe infantile form: progressive muscle weakness + hypotonia resulting from degeneration/loss of the lower motor neurons in spinal cord + brain stem nuclei

ORPHA:83418 SMA type 2

Prevalence: 1-9/100 000 (prevalence 1/70 000, slightly more frequent in males than females)

Chronic infantile form: muscle weakness + hypotonia resulting from degeneration/loss of lower motor neurons in the spinal cord + brain stem nuclei

ORPHA:83419 SMA type 3

Prevalence: 1-9/1 000 000 (1/375000)

Relatively mild form: muscle weakness + hypotonia resulting from degeneration/loss of lower motor neurons in the spinal cord + brain stem nuclei

ORPHA:83420 SMA type 4

Adult-onset form: muscle weakness + hypotonia resulting from the degeneration/loss of lower motor neurons in the spinal cord + brain stem nuclei

• Alias: Infantile spinal muscular atrophy
• Alias: Proximal spinal muscular atrophy type 0, 1-4
• Alias: Spinal muscular atrophy-0, -1-4 [SMA]
• Alias: Werdnig-Hoffmann disease
• Allelic: Amyotrophic lateral sclerosis 8 (VAPB)
• Allelic: Amyotrophic lateral sclerosis, susceptibility to (DCTN1)
• Allelic: Androgen insensitivity (AR)
• Allelic: Androgen insensitivity, partial, with/-out breast cancer (AR)
• Allelic: Avascular necrosis of femoral head, primary, 2 (TRPV4)
• Allelic: Barrett esophagus/esophageal adenocarcinoma (ASCC1)
• Allelic: Brachyolmia type 3 (TRPV4)
• Allelic: Cardiomyopathy, dilated, 3B (DMD)
• Allelic: Charcot-Marie-Tooth disease, RI C (PLEKHG5)
• Allelic: Charcot-Marie-Tooth disease, axonal, type 20 (DYNC1H1)
• Allelic: Charcot-Marie-Tooth disease, axonal, type 2S (IGHMBP2)
• Allelic: Digital arthropathy-brachydactyly, familial (TRPV4)
• Allelic: Encephalopathy, progressive, +/- lipodystrophy (BSCL2)
• Allelic: Farber lipogranulomatosis (ASAH1)
• Allelic: Fetal akinesia deformation sequence 2 (RAPSN)
• Allelic: Fetal akinesia deformation sequence 3 (DOK7)
• Allelic: Frontotemporal dementia and/or amyotrophic lateral sclerosis 2 (CHCHD10)
• Allelic: Hereditary motor + sensory neuropathy, type IIc (TRPV4)
• Allelic: Hex A pseudodeficiency (HEXA)
• Allelic: Hypospadias 1, XL (AR)
• Allelic: Lipodystrophy, congenital generalized, type 2 (BSCL2)
• Allelic: Menkes disease (ATP7A)
• Allelic: Mental retardation, AD 13 (DYNC1H1)
• Allelic: Metatropic dysplasia (TRPV4)
• Allelic: Occipital horn syndrome (ATP7A)
• Allelic: Parastremmatic dwarfism (TRPV4)
• Allelic: Prostate cancer, susceptibility to (AR)
• Allelic: Scapuloperoneal spinal muscular atrophy (TRPV4)
• Allelic: Sodium serum level QTL 1 (TRPV4)
• Allelic: Spondyloepiphyseal dysplasia, Maroteaux type (TRPV4)
• Allelic: Spondylometaphyseal dysplasia, Kozlowski type (TRPV4)
• Amyotrophic lateral sclerosis 4, juvenile (SETX)
• Becker muscular dystrophy (DMD)
• Brown-Vialetto-Van Laere syndrome 2 (SLC52A2)
• Charcot-Marie-Tooth disease, axonal, type 2F (HSPB1)
• Charcot-Marie-Tooth disease, axonal, type 2L (HSPB8)
• Charcot-Marie-Tooth disease, type 2D (GARS1)
• Duchenne muscular dystrophy (DMD)
• GM2-gangliosidosis, several forms (HEXA)
• Glycogen storage disease II (GAA)
• Muscular dystrophy, congenital, Davignon-Chauveau type (TRIP4)
• Myasthenia, congenital, 12, with tubular aggregates (GFPT1)
• Myasthenic syndrome, congenital, 10 (DOK7)
• Myasthenic syndrome, congenital, 11, associated with acetylcholine receptor deficiency (RAPSN)
• Myasthenic syndrome, congenital, 20, presynaptic (SLC5A7)
• Myasthenic syndrome, congenital, 4A, slow-channel + 4B, fast-channel (CHRNE)
• Myasthenic syndrome, congenital, 4C, associated with acetylcholine receptor deficiency (CHRNE)
• Myasthenic syndrome, congenital, 5 (COLQ)
• Myasthenic syndrome, congenital, 6, presynaptic (CHAT)
• Myasthenic syndrome, congenital, 7A, presynaptic, distal motor neuropathy, AD (SYT2)
• Myasthenic syndrome, congenital, 7B, presynaptic, AR (SYT2)
• Myopathy, isolated mitochondrial, AD (CHCHD10)
• Myotonic dystrophy 1 (DMPK_CTG)
• Neuronopathy, distal hereditary motor [MONDO:0000075] (EXOSC8)
• Neuronopathy, distal hereditary motor, type II (HSPB1)
• Neuronopathy, distal hereditary motor, type IIA (HSPB8)
• Neuronopathy, distal hereditary motor, type IID (FBXO38)
• Neuronopathy, distal hereditary motor, type IX (WARS1)
• Neuronopathy, distal hereditary motor, type VA (GARS1)
• Neuronopathy, distal hereditary motor, type VB (REEP1)
• Neuronopathy, distal hereditary motor, type VI (IGHMBP2)
• Neuronopathy, distal hereditary motor, type VIIA (SLC5A7)
• Neuronopathy, distal hereditary motor, type VIIB (DCTN1)
• Neuronopathy, distal hereditary motor, type VIII (TRPV)
• Neuropathy, distal hereditary motor, type VC (BSCL2)
• Perry syndrome (DCTN1)
• Pontocerebellar hypoplasia type 1A (VRK1)
• Pontocerebellar hypoplasia, type 1B (EXOSC3)
• Pontocerebellar hypoplasia, type 1C (EXOSC8)
• Silver spastic paraplegia syndrome (BSCL2)
• Spastic paraplegia 31, AD (REEP1)
• Spinal + bulbar muscular atrophy of Kennedy (AR_CAG)
• Spinal muscular atrophy with congenital bone fractures 1 (TRIP4)
• Spinal muscular atrophy with congenital bone fractures 2 (ASCC1)
• Spinal muscular atrophy with progressive myoclonic epilepsy (ASAH1)
• Spinal muscular atrophy, Jokela type (CHCHD10)
• Spinal muscular atrophy, XL 2, infantile (UBA1)
• Spinal muscular atrophy, distal, AR, 4 (PLEKHG5)
• Spinal muscular atrophy, distal, AR, 5 (DNAJB2)
• Spinal muscular atrophy, distal, XL 3 (ATP7A)
• Spinal muscular atrophy, infantile, James type (GARS1)
• Spinal muscular atrophy, late-onset, Finkel type (VAPB)
• Spinal muscular atrophy, lower extremity-predominant 1, AD (DYNC1H1)
• Spinal muscular atrophy, lower extremity-predominant, 2A + 2B, AD (BICD2)
• Spinal muscular atrophy, type 0 [prenatal] (SMN1)
• Spinal muscular atrophy, type III, modifier of (SMN2)
• Spinocerebellar ataxia, autosomal recessive, with axonal neuropathy 2 (SETX)
• Tay-Sachs disease (HEXA)