IllnessSpinal muscular atrophy, type 0, I, II, III, IV; differential diagnosis

Step 1: CNV analysis

DNA sequence analysis upon special request

NGS +

[Sanger]

Spinal muscular atrophy (SMA) is one of the most common autosomal recessive hereditary disorders in Europe with a statistical recurrence risk of 25%. SMA may be associated with early childhood death. The frequency of heterozygous carriers is reported to be 1/40 for the German population and ~1/50 worldwide (1,2). In the vast majority of affected children, loss of both SMN1 gene copies is the cause of disease. The parents then usually carry a deleted SMN1 gene copy on only one allele (obligatory heterozygosity). According to current knowledge, the different courses of SMA or the different ages of manifestation are significantly influenced by the number of copies of the chromosomally adjacent and nearly identical SMN2 gene present, with a broad spectrum of disease in addition to exceptions. Therefore, a phenotypic characterization also with regard to the now basic treatability and prognosis into "non-sitter", "sitter" and "walker" has been established, which also includes the aspect of a multisystem disease and the interdisciplinary therapeutic management (3, 4).

In the absence of functional SMN1 copies, the number of SMN2 copies mostly correlates with the severity of the disease pattern; patients with milder SMA phenotype have in respective studies more SMN2 copies than patients with severe SMA phenotype. Yet reliable prediction of the phenotype cannot be made, though being important for SMN2 copy number-dependent therapies (5).

SMA is, in principle, treatable. Antisense oligonucleotide, gene replacement and/or "SMA small molecule" therapies and their combination are available in appropriate neuromuscular centers with expertise in SMA treatment. Newborn screening with the possibility of very early presymptomatic causal therapy initiation has been introduced in Germany since October 1, 2021.

In Germany, in addition to prenatal diagnosis, newborn screening and early causal therapy with improved outcome, the option of preimplantation genetic diagnosis is also available as part of a human genetic counseling and multidisciplinary treatment concept for couples with an already affected child. Currently, rare point mutations in the SMN1 gene (~4% of cases) cannot be detected in newborn screening.

References

(1) doi: 10.3233/JND-190428

(2) doi: 10.1146/annurev-genom-102319-103602

(3) doi: 10.1016/j.nmd.2017.11.005

(4) doi: 10.1016/j.nmd.2017.11.004

(5) http://www.ncbi.nlm.nih.gov/books/NBK1352/

Translated with www.DeepL.com/Translator (free version)

• 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)