IllnessSpinale Muskelatrophie Typ 0, I, II, III, IV; Differentialdiagnose

Step 1: CNV analysis

DNA sequence analysis upon special request

NGS +

[Sanger]

Disease information

Spinal muscular atrophy (SMA) is one of the most frequent autosomal recessively inherited diseases in Europe, the most severe course leads to early infantile death. The frequency of heterozygous carriers is 1/40 tos 1/60 for the European population. In cultures with high rates of consanguinity autosomal recessive diseases such as SMA observed often (1). The majority of affected children has lost both SMN1 gene copies as cause of disease. Hence the parents are mostly carriers of one lost SMN1 gene copy, i.e. only for one allele. The different courses of the SMA forms I to III and the varying age of onset are mainly determined by the copy number of the virtually identical SMN2 genes neighboring on the same chromosome. From the SMN2 gene only a small amount of full-length transcripts are produced (2, 3). - Several gene therapeutich approaches have been established oon this basis, like e.g. Nusinersen (SpinrazaTM). This medication increases as antisense oligonucleotid the production of the SMN transcript by improved splicing of the SMN2 mRNA, thus working exclusively if there are several copies of the SMN2 gene (4). Onasemnogene Abeparvovec (ZolgensmaTM) is a Adeno-associated virus 9 based gene therapy with which a transgene copy of the SMN1 gene is transfected, that codes for the SMN protein (5).

References: (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)