Spinal Muscular Atrophy (SMA)

Literature and regulatory information updated: 4 October 2026.

SMN1-related spinal muscular atrophy (5q SMA, types 0–4), the modifying role of SMN2, silent [2+0] carriers and differential diagnosis with non-5q forms

0. Initial Reference Table

1. Introduction

Spinal muscular atrophy (SMA) is an autosomal recessive neurodegenerative disorder characterised by degeneration of spinal anterior horn and brainstem motor nucleus alpha motor neurons, resulting in symmetrical, predominantly proximal weakness, hypotonia, absent or reduced reflexes and progressive muscle atrophy, with preserved intelligence [6–9]. Before disease-modifying treatment, SMA was the commonest genetic cause of infant death and the second most frequent severe autosomal recessive disorder in European ancestry populations after cystic fibrosis [7, 10]. Estimated birth incidence is approximately 1 in 10,000 live births and prevalence 1–2 per 100,000 population, with type 1 accounting for approximately 60% of incident cases [11].

SMA's history begins with Guido Werdnig in Graz, who in 1891 reported two siblings with progressive muscular atrophy beginning in the first year, interpreted as neural rather than myopathic [12], and Johann Hoffmann in Heidelberg, who between 1893 and 1900 described affected families, demonstrated anterior horn cell loss at autopsy and coined “spinal muscular atrophy” [13]. In 1956, Erik Kugelberg and Lisa Welander in Stockholm described slowly progressive juvenile disease resembling muscular dystrophy but shown by electromyography and muscle biopsy to be neurogenic [14]. The International SMA Consortium (Bonn, 1992) standardised clinical types by onset age and highest motor function; linkage analysis mapped the locus to 5q11.2-13.3 in 1990 [6, 15]. In 1995, Judith Melki and Arnold Munnich's Paris group identified SMN (survival motor neuron) within an approximately 500 kb inverted duplication at 5q13, showing the telomeric copy (SMN1) absent or disrupted in 226 of 229 patients and a nearly identical centromeric copy (SMN2) present in approximately 95% of controls [16]. In 1999, Lorson and colleagues and Monani and colleagues showed that a single protein-silent C>T transition in SMN2 exon 7 causes exon 7 exclusion from most transcripts and explains why SMN2 cannot compensate for SMN1 loss, paving the way for splicing modulation [17, 18].

The decade from 2016 to 2026 transformed SMA from a disorder whose prognosis was determined by natural history into a treatable condition. Nusinersen (Spinraza®), an intrathecal antisense oligonucleotide, was approved by the US Food and Drug Administration (FDA) on 23 December 2016 and the European Commission on 30 May 2017 [19, 20]; intravenous gene therapy onasemnogene abeparvovec (Zolgensma®) received FDA approval in May 2019 and European Union (EU) approval on 18 May 2020 [21, 22]; oral splicing modifier risdiplam (Evrysdi®) received FDA approval on 7 August 2020 and EU approval on 26 March 2021 [23, 24]. Between 2025 and 2026, approvals included the 5 mg risdiplam tablet, high-dose nusinersen regimen, intrathecal onasemnogene abeparvovec (Itvisma®) and, in the US, antimyostatin antibody apitegromab (Isembyld®) as adjunctive treatment [19, 25–30]. In parallel, newborn screening enabled presymptomatic treatment and created a new patient population whose clinical trajectories differ from the historical classification [31, 32].

2. Molecular Genetics and Pathophysiology

2.1. Genomic architecture of the 5q13 region

The 5q13.2 region contains an inverted segmental duplication of about 500 kb, each unit harbouring the SMN, NAIP, SERF1 and GTF2H2 genes. The telomeric copy contains SMN1 and the centromeric copy SMN2; both genes have nine exons (1, 2a, 2b, 3 to 8) and differ by only five to eight nucleotides, none of which alters the amino-acid sequence of the 294-residue protein [8, 16, 18]. The instability of the region, with repeats and pseudogenes, favours deletions, duplications and gene conversion, a non-reciprocal recombination process that replaces the sequence of one gene with that of its homologue [6]. For this reason, SMN1 copy number in the general population ranges from zero to four and SMN2 copy number from zero to eight; about 5% of healthy individuals have no copy of SMN2 [6, 8]. The French PNDS reports about 10% of individuals without SMN2 copies in the general population, twice the GeneReviews estimate, without identifying the reference population; absence of SMN2 has no phenotypic expression in people with normal SMN1 [1, 8].

2.2. SMN1 mutational spectrum

Wirth and colleagues found homozygous SMN1 exon 7 absence in 94% of clinically typical SMA patients; among patients with identifiable variants, 98% of pathogenic alleles represent exon 7 absence (deletion or conversion to SMN2) and 2% small intragenic variants [6, 33]. Approximately 3.6% of SMN1-related patients are compound heterozygotes for a deletion and an intragenic variant [6, 34]. Point variants cluster in exons 3 (Tudor domain) and 6 (YG domain), including missense variants such as p.(Tyr272Cys), identified by Lefebvre in 1995, and intron 6 and 7 splicing variants [8, 16]. De novo deletions occur in approximately 1.7%–2% of patients, implying only one parent is a carrier in these cases [6, 8]. As a loss-of-function mechanism, intragenic variants are classified under the American College of Medical Genetics and Genomics (ACMG) five-class framework (pathogenic, likely pathogenic, uncertain significance, likely benign, benign), with the additional difficulty of assigning a variant to SMN1 rather than SMN2, requiring specific long-range amplification or subcloning [8].

Residual genetic heterogeneity exists: Wirth and colleagues estimated that other genes cause disease in approximately 1.9% of type 1, 1.6% of type 2 and 13% of type 3 patients with typical clinical, electromyographic and histological findings [6, 34]. Gene panels, whole-exome sequencing (WES) or whole-genome sequencing (WGS) are therefore warranted when SMN1 and SMN2 analysis is normal [6].

2.3. SMN2 as modifier and treatment target

The critical functional difference between the two genes is the c.840C>T transition (historical designation C6T; paralogous difference between NM_000344.4 of SMN1 and NM_017411.4 of SMN2, in which reference nucleotide c.840 is already T) at position +6 of exon 7 of SMN2: thymine weakens an SF2/ASF-dependent exonic splicing enhancer and creates a silencer recognised by the ribonucleoprotein hnRNP A1, so that about 90% of SMN2 transcripts exclude exon 7 (SMNΔ7) and give rise to a truncated, unstable protein with reduced oligomerisation capacity that is rapidly degraded [8, 17, 18]. Each SMN2 copy therefore produces only a fraction (of the order of 10%) of full-length SMN protein, and the total amount available to the patient is roughly proportional to copy number [35]. In Feldkötter's series, 80% of patients with type 1 had one or two SMN2 copies, 82% of patients with type 2 had three copies and 96% of patients with type 3 had three or four copies; among 113 patients with type 1, nine with one copy lived less than 11 months, 88 of 94 with two copies lived less than 21 months and eight of ten with three copies lived 33 to 66 months [35]. The compilation by Calucho and colleagues, with 3459 patients, confirmed the correlation and its overlap between categories, which limits individual predictive value [36]. Copy number is not the only determinant: the variant NM_017411.4:c.859G>C p.(Gly287Arg) in exon 7 of SMN2 creates a new splicing enhancer, increases the production of full-length transcripts and has been identified in patients with a milder phenotype than predicted by copy number [37]. Other modifiers studied include the protective genes PLS3 (plastin 3) and NCALD (neurocalcin delta), described in asymptomatic carriers of homozygous SMN1 absence [8]. The PNDS stresses that the protective effect of PLS3 overexpression on survival in mouse models is controversial, that CORO1C, NCALD and CHP1 await replication studies and that no role in disease severity has been demonstrated for NAIP or GTF2H2, genes neighbouring SMN1 [1].

2.4. SMN protein function and pathophysiology

Ubiquitously expressed SMN is the central component of the SMN complex (with gemins 2–8 and UNRIP), assembling Sm proteins on small nuclear RNA (snRNA) to form spliceosomal ribonucleoproteins. It also participates in U12-type intron splicing, axonal messenger RNA transport, RNA–DNA hybrid (R-loop) resolution and neuromuscular junction homeostasis [8, 38]. Lower motor neurons, with long axons and substantial transport and synaptic maintenance requirements, are most vulnerable to reduced SMN. In type 1, motor neuron loss is detectable from 12 gestational weeks and accelerates neonatally [6]. Denervation produces grouped muscle fibre atrophy with compensatory type 1 fibre hypertrophy and collateral reinnervation; compound muscle action potential (CMAP) amplitude and motor unit number estimation (MUNE) fall early, indicating motor neuron reserve, while serum or CSF neurofilament light chain (NfL) reflects active axonal degeneration [39–41]. SMN deficiency also has extraneuronal effects, especially in severe forms: structural cardiac abnormalities and arrhythmias with one SMN2 copy, distal vascular changes, pancreatic and hepatic dysfunction (with fasting- or illness-related hypoglycaemia and metabolic acidosis with dicarboxylic aciduria), and bone abnormalities [8, 42].

Thus, 5q SMA is a dosage disorder: complete SMN absence (zero SMN1 and zero SMN2 copies) is embryonically lethal, and phenotype severity forms a continuum reflecting residual protein production by SMN2 copies [7, 8]. This relationship underpins two treatment strategies: increasing full-length protein from SMN2 (nusinersen, risdiplam) or providing a functional SMN1 copy (onasemnogene abeparvovec) [38].

2.5. IGHMBP2 and spinal muscular atrophy with respiratory distress type 1 (SMARD1)

The IGHMBP2 gene (immunoglobulin mu DNA binding protein 2; OMIM *600502; MANE Select transcript NM_002180.3) is located at 11q13.3, has 15 exons and encodes a protein of 993 amino acids (about 109 kDa), an ATP-dependent helicase of superfamily 1, UPF1-like group, which unwinds DNA and RNA duplexes with 5'→3' polarity [3, 4]. The protein has a helicase domain with two RecA-like subdomains and at least seven conserved motifs, an R3H domain binding single-stranded nucleic acids, whose interaction with the helicase domain increases RNA affinity and ATPase activity, and an AN1-type zinc finger; it is ubiquitously expressed, mainly in the cytoplasm, where it associates with ribosomes [4]. Proposed functions include processing and maturation of messenger RNA and ribosomal RNA and regulation of translation, but the mechanism of the selective vulnerability of the alpha motor neuron and the phrenic nerve remains unclear [4, 43].

In 2001, Grohmann and colleagues demonstrated, in six families, recessive IGHMBP2 missense variants (exons 5, 11 and 12), nonsense variants (exons 2 and 5), a frameshift variant (exon 5) and a donor splice-site variant (intron 13), and linked the disease to the nmd (neuromuscular degeneration) mouse, which carries a spontaneous Ighmbp2 variant and shows motor neuron degeneration and hind-limb paralysis; IGHMBP2 thus became the second gene associated with a spinal muscular atrophy, after SMN1 [4, 44]. Inheritance is autosomal recessive, with biallelic variants in the homozygous or compound heterozygous state; heterozygous carriers are asymptomatic [44, 45].

The mutational spectrum includes missense, nonsense and splicing variants, small deletions and insertions and larger rearrangements [3]. In the retrospective study by Guenther and colleagues, sequencing of the entire coding region in 141 patients with an SMA phenotype and respiratory distress identified IGHMBP2 variants in 47 (33%); all missense variants altered conserved residues in or near the helicase domain, and the splicing variant NM_002180.3:c.1235+3A>G retained a residual normal messenger RNA level of 24.4% ± 6.9%, insufficient to prevent SMARD1 [46]. Eckart and colleagues found that the variants of patients with a better course retained residual enzymatic activity when expressed in a recombinant system [47]. Detection of deep intronic variants requires genome sequencing and RNA analysis: Bodle and colleagues described the first patient with SMARD1 caused by a deep intronic variant, not detectable by exome [48]. In the series by Pitt and colleagues, two of the eight patients tested had only one heterozygous variant identified, which is consistent with a second allele not detected by the methods of the time [49]. Recurrent variants occur in specific populations: in a Chinese series of three patients, NM_002180.3:c.1060G>A p.(Gly354Ser) was found in two unrelated patients and proposed as a possible recurrent variant in that population [50].

Biallelic IGHMBP2 variants also cause axonal Charcot-Marie-Tooth disease type 2S (CMT2S), described by Cottenie and colleagues in 11 families with slowly progressive axonal neuropathy, sensory loss and no significant respiratory involvement [51]. In CMT2S, combinations of a nonsense variant in the 5' region of the gene with a truncating, missense or frameshift variant in the last exon predominate; IGHMBP2 protein levels in fibroblasts and lymphoblastoid lines are higher than in SMARD1 and lower than in controls, suggesting that the phenotype depends on the amount of residual protein [4, 51]. The spectrum is continuous: Bektaş and colleagues described, in three Turkish families, a premature infant with typical SMARD1, a child with infantile-onset neuropathy without respiratory symptoms and two siblings with a Guillain-Barré syndrome-like presentation (cauda equina enhancement, raised CSF protein and acute motor and sensory axonal neuropathy), with an initial response to intravenous immunoglobulin [52].

SMARD is genetically heterogeneous: not all patients with the phenotype have IGHMBP2 variants [46, 53]. Butterfield and colleagues identified by exome sequencing, in an infant with congenital motor neuron disease and early death from respiratory failure, a de novo variant in the X-linked gene LAS1L, published as p.S477N (published designation, without confirmed conversion to the reference transcript), which is involved in processing of the 45S pre-rRNA and maturation of the 60S ribosomal subunit; the zebrafish model supported pathogenicity, and the entity is designated SMARD2 (ORPHA:404521) [54]. Altered ribosome maturation has been proposed as a mechanism common to both forms [54].

3. Clinical Spectrum and Manifestations by System

3.1. Clinical classification

The classic classification uses onset age and highest motor function achieved without disease-modifying treatment; GeneReviews and the Oxford Desk Reference emphasise a continuum rather than discrete conditions [6, 8]. The following table integrates the Oxford Desk Reference, Síndromes Genéticas: Reconhecer para Tratar, GeneReviews and natural history series.

Sources: [6–8, 35, 39, 40, 55].

Type 0 presents with reduced fetal movements, arthrogryposis multiplex congenita, severe hypotonia, respiratory failure from birth and sometimes congenital heart disease (atrial septal defects) [6, 8]. The Oxford Desk Reference notes that approximately 50% of newborns with SMA-associated arthrogryposis have homozygous SMN deletions, most patients with SMN abnormalities are hypotonic without birth contractures, and larger 5q deletions are associated with contractures [56]. SMA is not associated with fetal akinesia sequence beginning early in pregnancy, but should be considered in surviving newborns with late-onset prenatal signs and infants with homozygous SMN1 absence, low SMN2 copy number and arthrogryposis [53].

Type 1 begins before 6 months; natural history studies reported median age to death or permanent ventilation of 13.5 months in Finkel's cohort (interquartile range 8.1–22.0) and 8 months in infants with two SMN2 copies in NeuroNEXT [39, 40]. Among 33 conventionally treated type 1 infants, none achieved major milestones such as rolling or unsupported sitting, providing the comparator for disease-modifying treatments [6]. Approximately one third of mothers report reduced fetal movements [6].

The French PNDS subdivides type 1 according to age at onset and head control: 1A, with onset between birth and 15 days of life, severe weakness of subacute onset, sucking and swallowing difficulties and respiratory distress; 1B, with onset before 3 months and without acquisition of head control; and 1C, with onset between 3 and 6 months and possible head holding, designated «type I bis» in French practice [1]. Forms 1A and 1B are distinguished by rapidly progressive respiratory failure and brainstem involvement: dysphagia (to be suspected in the presence of pharyngeal stasis, coughing during meals or food selection by the child), dysphonia, nasal voice, tongue fasciculations and atrophy, facial involvement and vasomotor disturbances; a maximal interincisal distance below 35 mm, micrognathia with retrognathia and a high-arched palate are markers of bulbar involvement [1]. In a French two-centre retrospective study cited by the PNDS, brainstem involvement was present in 57% of patients, with 84% in type 1, 57% in type 2 and 24% in type 3 [1]. Dysautonomia, frequent in type 1, manifests as episodes of severe symptomatic bradycardia, blood pressure fluctuations, vasomotor disturbances with temperature changes and, rarely, distal necroses of vascular origin; finger fasciculations are visible in about one third of infants [1]. In a French multicentre retrospective series of 222 infants with early type 1 followed over 20 years, before disease-modifying therapies, the mean age at first signs was 2.1 months and the mean age at death 8.1 months, and 10% of children died suddenly, probably from acute brainstem dysfunction [1].

Type 2 manifests between 6 and 18 months; the child sits when placed but does not stand or walk independently. In Zerres's collaborative series, which included 569 patients with types 2 and 3, survival in type 2 was 98.5% at 5 years and 68.5% at 25 years [55]. Type 3 is divided into 3a (onset before 3 years) and 3b (onset after 3 years): the probability of retaining ambulation 10 and 40 years after onset was 70.3% and 22.0% in type 3a and 96.7% and 58.7% in type 3b, with life expectancy similar to that of the general population [55]. Type 4, of adult onset, causes mild proximal weakness and fatigue, with no impact on survival [8]. According to the PNDS, type 0 accounts for about 3.5% of all types; in type 3, hand tremor is frequent, tongue fasciculations are rare and reflexes may be preserved; type 4 begins between the second and third decade, with initial pelvic girdle weakness and waddling gait, later extending to all four limbs and the trunk [1]. The PNDS estimates that 73% of patients with type 1 have two SMN2 copies, 78% of patients with type 2 have three copies and, in type 3, 49% have three and 44% four copies, a distribution close to Feldkötter's series (section 2.3) [1, 35].

With newborn screening and presymptomatic treatment, historical classification has less prognostic value. Proposed nomenclature combines genotype (SMN2 copy number), clinical status (presymptomatic or symptomatic), treatment onset age and current motor function (nonsitter, sitter, walker) [31, 32, 57].

3.2. Manifestations by system

Neuromuscular system. Weakness is symmetrical, proximal more than distal and predominantly lower-limb; facial and ocular muscles are relatively spared, producing an alert gaze despite limb paralysis in infants [6, 7]. Tongue fasciculations are frequent in type 1, and fine postural hand tremor (minipolymyoclonus) characterises type 2 [7, 8]. Tendon reflexes are usually absent in types 0 and 1 and reduced in types 2 and 3, but preserved reflexes do not exclude disease [6, 58]. Síndromes Genéticas: Reconhecer para Tratar describes a course distinguishing SMA from other motor neuron disorders: a presymptomatic period, rapidly progressive functional loss, then stabilisation or transient improvement, with deterioration under stresses such as pregnancy or infection [7].

Respiratory system. Weakness of the intercostal muscles with relative sparing of the diaphragm results in a bell-shaped chest, paradoxical breathing (chest depression and abdominal protrusion on inspiration), ineffective cough, recurrent respiratory infections, nocturnal hypoventilation and respiratory failure, the main cause of death in types 1 and 2 [7, 8, 42]. The PNDS adds that paralysis of the respiratory muscles before the age of 4 years causes pulmonary hypoplasia through reduced alveolarisation, that inspiratory weakness deforms the chest (upper narrowing and verticalisation of the ribs, a keel-shaped appearance in the middle third and a flared bell shape at the base), that the retrognathia of type 1 and the midface hypoplasia caused by prolonged use of the non-invasive ventilation mask obstruct the upper airways and that, in type 2, respiratory failure is later but constant before adulthood [1]. Respiratory failure at birth is rare in type 1 and, when present, should suggest type 0 or a differential diagnosis, such as congenital myotonic dystrophy or SMA with respiratory distress (SMARD1), in which diaphragmatic paresis is early [58].

Digestive system and nutrition. Bulbar weakness causes dysphagia, aspiration, gastro-oesophageal reflux, slow gastric emptying and constipation; in type 1 the need for nutritional support precedes the need for ventilatory support [7, 40]. In type 2, feeding difficulties and aspiration-related respiratory infections may occur, with some patients requiring gastrostomy [6]. In ambulant patients the risk of excess weight predominates, and metabolic changes such as hyperleptinaemia have been described in type 3 [7, 57]. According to the PNDS, in type 2 chewing difficulties affect 20% to 28% of patients, dysphagia with aspiration 25% to 30% and progressive limitation of mouth opening 30%, due to facial paralysis and masseter retraction, which hampers feeding, dental care and tracheal intubation; 37% of patients with type 2 have a weight below −2 standard deviations and 5% above +2 standard deviations, and fat mass increases at the expense of lean mass, with a risk of excess weight in patients with type 2 and good motor function and in patients with type 3 [1]. Motility disorders include constipation, reflux, gastroparesis with slow gastric emptying and, in extreme cases, chronic intestinal pseudo-obstruction; in severely emaciated patients with persistent vomiting, once constipation has been excluded, superior mesenteric artery syndrome should be considered (compression of the third part of the duodenum between the superior mesenteric artery and the aorta, due to loss of perivascular adipose tissue) [1]. Acute gastric dilatation, of dysautonomic origin, may occur at any age during a viral illness, prolonged supine decubitus or other stress, with severe abdominal pain, repeated vomiting, severe dehydration within a few hours, metabolic acidosis and hypoglycaemia (section 7.10) [1].

Musculoskeletal system. Neuromuscular scoliosis affects about half of non-ambulant patients before the age of 10 years, with curves greater than 50 degrees, worsening respiratory function; hip dislocation, joint contractures, limited range of motion and reduced bone mineral density with low-impact fractures occur [6, 8, 57, 59]. The PNDS reports scoliosis in 60% to 90% of patients with types 1 and 2 and in about 50% of patients with type 3; in type 2 it usually begins at around 3 years and in type 3 mainly after loss of ambulation; pain associated with deformities affects up to 60% of patients and worsens during transfers, care and rehabilitation, and fractures occur in types 1 and 2 and also in ambulant adolescents with type 3, in whom prolonged immobilisation may precipitate loss of ambulation [1]. The SMN protein interacts with osteoclast-stimulating factor, so osteopenia does not result solely from weakness and immobility [1].

Metabolism. During prolonged fasting or acute illness, hypoglycaemia and metabolic acidosis with dicarboxylic aciduria and low carnitine may occur, so prolonged fasting should be avoided, especially perioperatively [8, 42]. The PNDS also reports abnormalities of fatty acid metabolism, hyperlipidaemia, hyperglycaemia or hypoglycaemia, mitochondrial dysfunction and abnormalities of glucose metabolism and pancreatic development in the mouse model, confirmed in some obese patients [1].

Cognition. Intelligence is normal; the study by von Gontard (2002) found that environment-dependent aspects of intelligence were higher than in controls in adolescents with SMA [6, 7]. In the German study of 96 patients aged 6 to 18 years with types 1 to 3 cited by the PNDS, cognitive abilities below the age of 12 did not differ from those of controls and, in adolescents, verbal quotient (113 versus 104) and full-scale quotient (109 versus 95) were higher, without excess psychiatric comorbidity, although separation anxiety was frequent; siblings had a rate of behavioural problems three times that of the general population [1]. In a small French group of children aged 3 to 4 years with type 2, language developed earlier and vocabulary was richer than in age-matched controls [1].

Pregnancy. Successful pregnancies have been described in women with type 2; lung function may remain stable during pregnancy and deteriorate transiently after delivery [6]. According to the PNDS, motor worsening occurs in about 65% to 75% of pregnancies, mainly in the second trimester, and persists after delivery in about one third; it relates more to the speed of prior progression than to age at onset and is more frequent in type 2 than in stabilised type 3; preterm delivery occurs in just under one third of pregnancies, caesarean section in 20% to 42% and instrumental delivery in 18%, with no excess of non-cephalic presentations (about 18%) or of neonatal cerebral distress; management is described in section 7.10 [1].

Emerging phenotypes in treated patients. Treated type 1 children have new phenotypes: prolonged survival with residual weakness, dysphagia, early scoliosis, contractures and, with one or two SMN2 copies, extraneuronal cardiac and distal vascular manifestations not observable in natural history [8, 38].

Urinary and endocrine systems. The PNDS describes urinary lithiasis and a sensation of incomplete bladder emptying in adolescents and young adults, a compliant, large-capacity bladder in the few urodynamic studies and rare cases of incontinence in severe forms; cryptorchidism affects about one third of boys with types 1 and 2, with normal hormonal assessment; puberty and menarche occur at the expected age, and premature pubarche has been described in 24% of children with types 1 and 2, exceptionally with hyperandrogenism and with a higher insulin resistance index [1].

Adulthood and participation. In a survey of 359 adults with SMA cited by the PNDS (Mongiovi and colleagues, 2018), 98% reported limited mobility, 96% limb weakness and about 70% fatigue; respiratory difficulties (100% and 79%), swallowing difficulties (100% and 76%) and communication difficulties (80% and 32%) predominated in types 1 and 2 [1]. Pain is more frequent than in the general population in all types (one third of patients with type 2 in the series by Jeppesen and colleagues, mainly due to uncomfortable sitting position; 63% in type 4), fatigue is more marked than in other neuromuscular diseases and does not correlate with fatigability or function, motor function continues to deteriorate in all types and at all ages, and adults with type 3 report bulbar worsening after the age of 30 [1]. In a Dutch study, later-onset forms were associated with more stress and anxiety and with poorer quality of life than early forms, which led the PNDS to recommend psychological surveillance targeted at moderate adult forms [1]. In the PRISM-SMA study, 75% of adults had higher education, 23% up to master's or doctoral level; in the Rhône cohort, about half of patients with types 2 and 3 were in employment, more than 90% lived in their own home (1 in 52 in a medico-social facility), and 60% of patients with type 3 lived as a couple, versus 30% in severe types 2 and 3, a value close to the 24% described in type 2 in a Danish cohort [1]. The well-being of these adults correlated with participation, autonomy and social connectedness, and not with disease characteristics [1].

3.3. SMARD1: clinical spectrum and natural history

SMARD1 was described by Mellins in 1974 as a variant of SMA with respiratory onset and was only recognised as a distinct entity in the 1990s [3, 4]. There is no specific neonatal sign, but intrauterine growth restriction and prematurity are frequent; weak cry, hypotonia, feeding and sucking difficulties, recurrent respiratory infections and congenital foot deformities appear in the first weeks [4, 45]. In the series of 29 infants by Grohmann and colleagues, the earliest signs were intrauterine growth restriction, weak cry and foot deformities, and most presented between the 1st and 6th month with respiratory distress due to diaphragmatic paralysis and progressive, predominantly distal weakness of the lower limbs, with involvement of sensory and autonomic nerves [45].

Respiratory distress, usually the presenting sign, occurs between 6 weeks and 6 months due to neurogenic diaphragmatic paralysis and manifests as inspiratory stridor, weak cry, recurrent bronchopneumonia and feeding difficulty; it may be triggered by a respiratory infection and is almost always life-threatening without intervention [3, 4]. Unlike 5q SMA, in which intercostal weakness with a preserved diaphragm produces a bell-shaped chest and paradoxical breathing, in SMARD1 the chest has a normal shape, because the deficit mainly affects the diaphragm [4, 60]. Chest radiography shows elevation (eventration) of the right hemidiaphragm or, less frequently, of both [4]. Weakness begins in the distal muscles, first in the lower limbs, and later extends to proximal muscles; it progresses to tetraparesis with areflexia, as a rule after the first year, equinovarus feet, wrist drop, distal contractures, kyphoscoliosis and accumulation of adipose tissue on the proximal phalanges (fatty finger pads) [4, 61]. Tongue fasciculations have been recorded in about 30% of patients; the oculomotor nerves are spared [3, 4]. Cognition is normal in most patients [3, 62].

Autonomic involvement is frequent and progressive: urinary incontinence or retention requiring catheterisation, excessive sweating, constipation, gastroparesis, cardiac arrhythmias and arterial hypertension [3, 4, 61]. In the series by Rudnik-Schöneborn and colleagues, of 6 patients with prolonged survival on ventilation (4.5 to 11 years), onset occurred in the first 2 months, permanent ventilation was started 2 to 8 months later, three patients had voiding dysfunction with reflux nephropathy and two had arrhythmia, hypertension and excessive sweating; loss of function occurred in the first year, with no subsequent progression recorded [61]. A catastrophic autonomic crisis with cardiac collapse has been described in a Japanese child [4].

Quantified data on the course come from small cohorts. In the longitudinal study by Eckart and colleagues (Berlin; 11 patients followed for a mean of 7.8 years, standard deviation 3.2), loss of autonomous breathing and onset of weakness occurred between 2 and 9 months, all patients were ventilated by 9 months, only one recovered spontaneous breathing for 12 hours a day, none achieved standing or walking and all had autonomic failure, in one case only after 9 years; the clinical score fell rapidly until 2 years and then stabilised or improved, and the score at 3 months correlated with the course at years 1 and 4 [4, 47]. At the end of follow-up, 7 of the 11 had normal facial expression, 4 sat and held their head, 6 spoke through the tracheostomy cannula, all but one lived at home and two thirds attended nursery or school; echocardiography was normal in the 7 patients studied [4, 47]. In the French multicentre study by Viguier and colleagues (30 centres, 22 paediatric observations), diaphragmatic paralysis was diagnosed a mean of 1.5 months after the first respiratory symptoms, hypotonia preceded areflexia by 4 months and onset before 3 months was associated with a worse prognosis; of the 6 living patients, all had a tracheostomy, only one survived beyond 2 years without artificial ventilation and the others died at a median of 7 months [63].

Three forms are distinguished according to age at onset: early (before 3 months), the most severe; classic (between 3 and 12 months); and late (after 12 months), milder and slowly progressive [3, 4]. Hamilton and colleagues described a 21-year-old woman with late-onset SMARD1, diagnosed at 16 months with mild eventration of the right hemidiaphragm after she had crawled and pulled to stand, with stable weakness, normal cognition, ventilation only at night and a socially integrated life [4, 62]. These data describe patients without targeted therapy, ventilated by decision of families and teams; they do not estimate the survival of all patients, because the series bring together cases referred to centres and survivors.

4. Clinical Recognition and Warning Signs

Early recognition is decisive because motor neuron loss is irreversible and all treatment benefits are inversely proportional to disease duration at treatment initiation [64, 65]. The Oxford Desk Reference structures assessment into three components: a three-generation family history covering consanguinity, SMA and unexplained infant deaths; pregnancy history (late reduction of fetal movement), delivery, milestones, symptom onset age, mobility loss and scoliosis; and targeted neurological examination [6].

Infant warning signs include a “frog-leg” posture from pelvic girdle weakness, hypotonia with few spontaneous limb movements but preserved small finger and toe movements, weak or absent kicking and poor limb withdrawal to painful stimulation, tongue fasciculations, areflexia, weak crying and coughing, paradoxical breathing, and sucking/swallowing difficulties, with preserved facial expression and alert gaze [6, 7, 58]. In hypotonic infants, the Oxford Desk Reference distinguishes central hypotonia (lethargy, relatively preserved limb strength, vigorous supine kicking) from peripheral hypotonia (alertness, static hypotonia over hours or days, areflexia). In type 1 SMA the face is spared, unlike congenital myotonic dystrophy and several congenital myopathies [58].

In children and adults, warning signs include delayed or regressing motor milestones, difficulty rising from the floor with Gowers' manoeuvre, waddling gait, frequent falls, stair-climbing difficulty, fine hand tremor, limb fasciculations and hyporeflexia with preserved sensation [6, 7]. Serum creatine kinase (CK) is normal or mildly elevated; in type 3 it may reach 20 times normal, leading to mistaken muscular dystrophy diagnosis [7].

In Portugal and other screening countries, most cases are now identified presymptomatically. Warning signs remain relevant to three groups: unscreened newborns (born before implementation, abroad or following refusal), compound heterozygotes for a deletion and point variant (approximately 5%, missed by exon 7 absence screening), and screened infants with four or more SMN2 copies under surveillance [32, 66, 67]. Normal CK, neurogenic electromyography or negative screening does not exclude diagnosis with a compatible phenotype [8].

The French PNDS stresses that the diagnosis is, in most cases, strongly suggested by the clinical picture: generalised hypotonia, bright gaze and good interaction, which exclude a central origin, tongue fasciculations with tremor of the extremities and, in type 1, paradoxical breathing with a preserved diaphragm; the respiratory and digestive signs to be systematically sought at each visit are coughing during meals or food selection (indicative of aspiration), nocturnal cough, signs of nocturnal hypercapnia (restless sleep, sweating, headache and fatigue on waking), recurrent respiratory infections and weight faltering [1]. The PNDS places CK elevation at up to 5 to 6 times normal, whereas Síndromes Genéticas: Reconhecer para Tratar allows values up to 20 times normal in type 3; in both cases, a raised CK does not exclude SMA and may lead to a misdiagnosis of muscular dystrophy [1, 7].

Sources: [6, 7, 45, 56, 58, 68–70].

SMARD1 should be considered in an infant with respiratory failure between 6 weeks and 6 months, a normally shaped chest, elevation of one hemidiaphragm (usually the right) and predominantly distal weakness, especially if there is intrauterine growth restriction, prematurity, weak cry, stridor or foot deformities [4, 46]. Chest radiography may be normal at the onset of respiratory distress: in at least 4 of the 22 patients in the French series there was no eventration at that time, and 28.6% had growth restriction and distal deformities at birth; therefore, a premature newborn with symmetrical growth restriction below the 10th centile and respiratory warning signs should prompt study of IGHMBP2 even without radiological abnormality [3, 4, 63]. SMARD1 is not detected by newborn screening for SMA, which tests only for absence of SMN1 exon 7 [3]. Grohmann and colleagues also recommended study of IGHMBP2 in the consanguineous parents of a child with sudden infant death [45].

5. Diagnosis: Criteria, Tests and Algorithms

5.1. Principles

5q SMA diagnosis is molecular. Homozygous SMN1 absence with a typical clinical presentation confirms diagnosis [6]. Part one of the international standards of care (Mercuri and colleagues, 2018) and GeneReviews establish this algorithm: quantify SMN1 exon 7 copies by multiplex ligation-dependent probe amplification (MLPA) or real-time quantitative PCR; zero copies confirms diagnosis; one copy with a compatible phenotype requires SMN1 sequencing to identify the second variant; two or more copies make 5q SMA unlikely and warrant investigation of other causes using CK, electromyography, nerve conduction and broader genetic testing [8, 57]. Conventional sequencing cannot distinguish SMN1 from SMN2, so an intragenic variant must previously have been described in SMN1 or confirmed in an SMN1-specific long-range PCR product or subclone; comparative genomic hybridisation (array) is unsuitable for this locus [8]. SMN2 copy number should always be determined because it informs prognosis and post-screening treatment decisions, although it has no diagnostic value [8, 71].

The Oxford Desk Reference summarises the practical sequence: DNA for SMN1/SMN2 dosage and variant analysis; next-generation sequencing panel, WES or WGS if SMN1/SMN2 findings are normal; CK to exclude muscular dystrophy unless molecular SMA diagnosis is established [6]. For hypotonic infants with suspected peripheral disease, it recommends CK (normal or mildly raised in SMA and congenital myopathies, raised in most congenital muscular dystrophies), electromyography and conduction velocities (fibrillation in SMA), and SMN1 exon 7 and 8 deletion testing [58].

The French PNDS adds practical rules: electroneuromyography is justified only in case of diagnostic doubt before genetic testing (neurogenic pattern with normal or slightly reduced motor and sensory conduction velocities); muscle biopsy is not indicated; all patients should have a report confirming biallelic inactivation of SMN1 and a report with the SMN2 copy number; in the absence of a homozygous deletion, specific techniques should be used to characterise the point variant; and, if the patient has died, the diagnosis can be confirmed indirectly by demonstrating a heterozygous SMN1 deletion in both parents [1]. Qualitative methods detect only the homozygous deletion and are those used in prenatal diagnosis; quantitative methods determine the copy number of SMN1 (for counselling) and of SMN2 (for patients); no available method distinguishes copies in cis from copies in trans, and copy-counting methods are not the same as those that identify point variants [1].

Sources: [1].

The 5% figure for compound heterozygosity is higher than the 3.6% in the series by Wirth and colleagues (section 2.2) [1, 6, 34].

5.2. Nonmolecular investigations

Sources: [7, 8, 39, 41, 58, 71].

5.3. SMN2 genotyping and sequencing-based methods

SMN2 copy number may be underestimated or overestimated because of interlaboratory technical differences, hybrid SMN1/SMN2 genes and probe-affecting variants. The 270th European Neuromuscular Centre (ENMC) workshop, held in 2023, established recommendations for reliable SMN2 copy-number determination in patients and screened newborns, modifier interpretation and laboratory kit manufacturers [72]. Dedicated genome-sequencing algorithms now determine SMN1 and SMN2 copy number: among 12,747 genomes, agreement with orthogonal methods was 99.8% for SMN1 and 99.7% for SMN2, with sensitivity of 100% for patients and 97.8% for carriers [73]. The 2024 North American and European diagnostic recommendations (SMA Update in Best Practices) unanimously included newborn screening in diagnostic best practice and defined minimum pretreatment characterisation of screened newborns [31].

5.4. Newborn screening

Newborn screening uses DNA extracted from the dried blood spot of the heel-prick test and real-time PCR targeting nucleotide NM_000344.4:c.840C in exon 7 of SMN1, detecting homozygous absence of exon 7 (by deletion or conversion), responsible for about 95% of cases; positive results are confirmed by a quantitative method that also determines SMN2 copy number [32]. The test does not identify compound heterozygotes (deletion and point variant) or carriers, and false positives due to SMN1 variants at the primer binding site have been described: Wirth and colleagues (2026) described two newborns, in Germany and Australia, with a single SMN1 copy carrying 4 bp deletions in exon 7 (NM_000344.4:c.855_858del and NM_000344.4:c.861_864del, both p.(Arg288AlafsTer5)), who were not treated and remained healthy at 24 months [67].

In France, at the time of the PNDS (2020), newborn screening for SMA was not organised; the PNDS cites the New York State pilot study, in which 93% of 3826 families without a history of SMA accepted the test, motivated by the benefit of presymptomatic diagnosis and by information for future pregnancies, whereas refusals invoked the potential impact on family cohesion [1].

In the US, SMA entered the Recommended Uniform Screening Panel (RUSP) in 2018; between 2018 and 2022, 30 states provided data on 6,244,825 newborns, with 425 confirmed cases (birth prevalence 1 in 14,694). Among 240 infants with known copy number, 5% had one SMN2 copy, 49% two, 33% three and 13% four or more [66]. In August 2024, 66% of newborns in geographical Europe and 64% in the EU were screened for SMA, with national programmes in several countries including Portugal [32].

In Portugal, the Instituto Nacional de Saúde Doutor Ricardo Jorge (INSA) began a national pilot in October 2022 involving 100,000 newborns; birth prevalence was 1:14,515 by the end of 2023 and 1:15,520 at completion in late 2024 [74, 75]. SMA (termed “atrofia muscular espinal” in the programme) entered the Programa Nacional de Rastreio Neonatal panel in January 2025, with sampling between days 3 and 6 and coverage above 99% [76]. Four cases were diagnosed in 2024 and ten in 2025 among 87,708 screened newborns [76, 77].

5.5. Treatment algorithm following newborn screening

The Cure SMA working group recommended immediate treatment for all infants with two or three SMN2 copies in 2018 [71]; in 2020 this expanded to four copies, retaining watchful surveillance for five or more [78]. For infants with one copy, usually symptomatic at birth, the treating clinician individualises the decision [71]. Parmova and colleagues' 2026 series of three patients with five SMN2 copies illustrates variability—one sibling with adult-onset proximal weakness, another asymptomatic, and a third patient with adolescent onset progressing to severe motor disability—and the need for longitudinal surveillance [79]. The original algorithm figure is openly accessible (https://pmc.ncbi.nlm.nih.gov/articles/PMC6004919/figure/jnd-5-jnd180304-g001/), with four-copy recommendations revised in 2020 [71, 78].

Sources: [8, 66, 71, 78, 79].

5.6. Prenatal diagnosis

Prenatal diagnosis by chorionic villus sampling at 11 weeks or amniocentesis is possible if the family molecular basis is known; both parents should be genotyped before sampling. Noninvasive haplotype-based prenatal diagnosis was under development at the time of the Oxford Desk Reference [6, 80]. Fetal SMN2 copy-number determination identifies severe cases potentially benefiting from treatment immediately after birth or, in future, fetal therapy [80].

The French PNDS describes the procedure: genetics clinic before any pregnancy in couples with a family history, with information on prenatal diagnosis, preimplantation genetic diagnosis and adoption; chorionic villus sampling between 11 and 13 weeks of gestation, with direct testing for homozygous SMN1 deletion combined with indirect diagnosis by microsatellite markers, which study allele segregation in the family and exclude maternal contamination of the fetal sample; and referral to one of the five French centres authorised for preimplantation genetic diagnosis (Paris, Strasbourg, Montpellier, Nantes and Grenoble) [1]. The report should answer only the question of whether or not the fetus is affected, without specifying whether an unaffected fetus is homozygous normal or a carrier [1]. In an Italian series of 314 fetuses, 30.3% were homozygous normal, 49% heterozygous and 20.7% affected, a deviation from the expected Mendelian proportion of 25% also observed in the annual reports of the French Agence de la biomédecine [1].

In the presence of ultrasound signs, the PNDS describes in type 0 reduced fetal mobility in the third trimester (56%), increased nuchal translucency with a normal karyotype in the first trimester (50%), heart disease (present in 75% of newborns, but difficult to detect prenatally), contractures in the third trimester (almost constant at birth) and, rarely, polyhydramnios; abnormal positioning of the extremities detected in the second trimester does not correspond to SMN1-related SMA [1]. No sign is sufficiently sensitive and specific for an algorithm, but reduced fetal movements at the end of the third trimester combined with at least one of these signs, especially heart disease, may justify testing for homozygous deletion in the fetus or heterozygous deletion in both parents; the late timing makes termination of pregnancy for medical reasons difficult [1]. The non-invasive prenatal diagnosis cited by the PNDS was based on a study of 6 pregnant women with a family history and 10 controls, with capture of variants in a 6 Mb interval around SMN1 in circulating fetal DNA, massively parallel sequencing and reconstruction of fetal haplotypes by comparison with the parents and the index case; it is an indirect method and a small series [1].

5.7. Genetic test limitations and report content

MLPA or quantitative PCR measures SMN1 and SMN2 exon 7 copies (and exon 8 with MLPA), but not their distribution across chromosomes: it cannot distinguish a [1+1] noncarrier from a silent [2+0] carrier, misses small intragenic variants responsible for approximately 2% of pathogenic alleles, and may be affected by hybrid SMN1/SMN2 genes or probe-site variants [6, 8, 72, 81]. Conventional sequencing and most short-read panels or exomes cannot reliably assign variants to SMN1 or SMN2 because the genes are nearly identical; comparative genomic hybridisation is unsuitable, and only dedicated algorithms validated against orthogonal methods can extract copy number from genome data [8, 73]. Real-time PCR newborn screening detects only homozygous exon 7 absence, missing compound heterozygotes and potentially producing primer-site false positives [32, 67]. Consequently, negative screening or one SMN1 copy does not exclude 5q SMA with a compatible phenotype, while two or more copies require investigation for non-5q disease [8].

Reports should state SMN1 and SMN2 copy numbers, method and limitations (including inability to detect [2+0] and the SMN2 intermethod variability highlighted by the 2023 ENMC consensus), versioned reference transcripts—NM_000344.4 for SMN1 and NM_017411.4 for SMN2, both MANE Select—HGVS nomenclature of intragenic variants (e.g. NM_000344.4:c.815A>G, p.(Tyr272Cys), classified as pathogenic or likely pathogenic in ClinVar), zygosity, phase when known and ACMG/AMP classification [8, 72, 82–84]. The functional exon 7 c.840 difference (C in SMN1, T in SMN2) was historically called “C6T”, referring to the sixth exon 7 nucleotide; both designations should be retained when citing pre-HGVS literature [17, 18]. SMN2 c.859G>C is a positive modifier and should not be interpreted as causal [37].

An intragenic SMN1 variant of uncertain significance does not become pathogenic because a patient responds to SMN2-targeting treatment (acting independently of the SMN1 variant) or because it is found in an affected sibling. Small-sibship segregation is weakly informative and should be described as investigational; relative carrier diagnosis should not rely on a VUS [8, 83].

5.8. Diagnosis of SMARD1

Diagnosis is based on the combination of the clinical picture, demonstration of diaphragmatic paralysis, neurophysiological findings and identification of biallelic IGHMBP2 variants; there is no specific biochemical biomarker [3, 4]. SMN1 quantification should precede or accompany the study, because 5q SMA type 1 is much more frequent; a result with two SMN1 copies in an infant with an SMA phenotype and respiratory distress points towards non-5q forms [6, 8]. Diaphragmatic paralysis is confirmed by thoracic ultrasound, fluoroscopy or diaphragm electromyography; eventration of the right hemidiaphragm on radiography is suggestive but may appear late: in the twin girls described by Leśniak and colleagues, paralysis was only documented by ultrasound at 4 years [3, 4].

The criteria of Pitt and colleagues (2003), developed from 13 infants with early diaphragmatic paralysis and progressive neuropathy, are still used to distinguish SMARD1 from similar conditions [4, 49]. Guenther and colleagues, by hierarchical cluster analysis in 141 patients with an SMA phenotype and respiratory distress, found that the combination «respiratory failure between 6 weeks and 6 months» and («diaphragmatic eventration» or «preterm birth») predicted the presence of IGHMBP2 variants with a sensitivity of 98% and a specificity of 92%; these values refer to a population already selected by an SMA phenotype with respiratory distress and not to the population of infants with respiratory failure [46]. The French series confirmed the predictive value of the Pitt criteria [4, 63].

Sources: [4, 49].

Molecular confirmation is by sequencing of IGHMBP2, alone or in a neuromuscular disease panel, exome or genome; if only one variant is identified, or none in a patient with a typical phenotype, intragenic deletions and duplications should be sought (MLPA or array comparative genomic hybridisation) and genome sequencing with RNA analysis for deep intronic variants should be considered [3, 48]. A negative result of coding sequencing does not exclude SMARD1, and a single heterozygous variant does not confirm it [48, 49]. Interpretation is limited by the frequency of variants of uncertain significance recorded in ClinVar for this gene; reclassification over time is possible, as with the variants NM_002180.3:c.595G>C p.(Ala199Pro) and NM_002180.3:c.1615_1623del p.(Ser539_Tyr541del), initially classified as of uncertain significance and later as likely pathogenic [3]. Parental segregation is necessary to confirm the trans configuration of the two variants [3]. The report should state the transcript (NM_002180.3), HGVS nomenclature, zygosity, phase demonstrated by segregation and the ACMG/AMP class of each variant. Once the two familial variants have been identified, prenatal diagnosis and preimplantation genetic diagnosis are possible [45].

6. Differential Diagnosis

6.1. Clinical differential diagnosis

Differential diagnosis depends on presentation age. Table 15.1.5 in Síndromes Genéticas: Reconhecer para Tratar groups alternatives into myopathies (dystrophinopathies, limb-girdle muscular dystrophies, metabolic and inflammatory myopathies), inflammatory neuropathies (including chronic inflammatory demyelinating polyneuropathy), neuromuscular junction disorders (myasthenia gravis and congenital myasthenic syndromes), hereditary sensorimotor neuropathies and other motor neuron disorders (non-5q SMA and late-onset hexosaminidase A deficiency) [7]. For hypotonic infants, the Oxford Desk Reference emphasises that central hypotonia is more common than peripheral, and congenital myotonic dystrophy is the commonest neonatal neuromuscular cause. Other considerations include Prader–Willi syndrome, congenital myopathies (nemaline, MTM1-related X-linked myotubular), congenital muscular dystrophies, Pompe disease, Zellweger syndrome, glycosylphosphatidylinositol deficiencies and Schaaf–Yang syndrome (MAGEL2) [58]. Adult alternatives include Kennedy disease (X-linked spinobulbar muscular atrophy caused by androgen receptor gene CAG expansion), amyotrophic lateral sclerosis [8] and late-onset hexosaminidase A deficiency (late-onset Tay–Sachs disease), whose motor neuron involvement may resemble SMA [7, 85].

The French PNDS organises the differential diagnosis by clinical type, based on four orienting features: generalised hypotonia, bright gaze, tongue fasciculations with tremor of the extremities and, in type 1, paradoxical breathing with a spared diaphragm [1].

Sources: [1, 58].

The PNDS describes the weakness of SMARD1 as predominant in the upper limbs, whereas the series by Grohmann and the review by Saladini (section 3.3) describe onset in the distal muscles of the lower limbs; the PNDS also reports absence of sensory involvement, whereas Grohmann documented involvement of sensory and autonomic nerves [1, 4, 45].

6.2. Non-5q spinal muscular atrophies

Non-5q SMAs are heterogeneous, with autosomal recessive, autosomal dominant or X-linked inheritance, and require investigation when SMN1 quantification shows two or more copies [6, 8]. Saudubray and colleagues include BICD2, DYNC1H1 and VAPB among cellular trafficking disorders causing SMA phenotypes through altered dynein-dependent retrograde axonal transport (BICD2 and DYNC1H1 are respectively an adaptor and heavy chain of the dynein–dynactin complex) and endoplasmic reticulum contact sites with other organelles (VAPB) [86].

Sources: [4, 6, 44, 45, 53, 56, 68–70, 86–95].

Grohmann and colleagues linked SMARD1 to biallelic IGHMBP2 variants in 2001. In their 29-infant series, earliest signs were intrauterine growth restriction, weak cry and foot deformities; most presented between months 1 and 6 with diaphragmatic paralysis-related respiratory distress and progressive, predominantly distal weakness [44, 45]. Saladini and colleagues' review found that most develop symptoms in the first year, permanent ventilatory support is usual and no effective approved treatment exists, although gene therapy has preclinical results [4]. Truncating and missense IGHMBP2 variants also cause a distinct condition, axonal Charcot–Marie–Tooth disease type 2S, without SMARD1's infantile respiratory failure [51].

X-linked infantile SMA was associated by Ramser and colleagues (2008) with missense variants and a recurrent synonymous variant (NM_003334.4:c.1731C>T p.(Asn577=), which reduces expression) in UBA1 (formerly UBE1), a gene of the ubiquitin-proteasome pathway [53, 88]. The Oxford Desk Reference recommends considering this diagnosis when findings suggest SMA, SMN MLPA is normal and there is evidence of X-linked transmission [56]. Post-zygotic somatic UBA1 variants at codon p.Met41 (published protein numbering) cause a distinct disease, VEXAS syndrome (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic), of late adult onset, without reproductive risk, which should not be confused with the germline form [96].

The 2024 GeneReviews chapter reclassified DYNC1H1-related disorders into neuromuscular disorder (formerly SMALED1 and CMT2O) and neurodevelopmental disorder (cortical malformations, epilepsy and intellectual disability), which may coexist. Harms and colleagues (2012) demonstrated that DYNC1H1 tail-domain variants cause dominant lower extremity-predominant SMA [68, 89]. Three simultaneous 2013 publications identified heterozygous variants in dynein motor adaptor BICD2 as a cause of congenital or childhood-onset autosomal dominant SMA overlapping hereditary spastic paraplegia [69, 90, 91].

The VAPB variant NM_004738.5:c.166C>T p.(Pro56Ser) was described by Nishimura and colleagues (2004) in a Brazilian family with late-onset SMA and in families with atypical ALS (ALS8) and rapidly progressive typical ALS [70]. In 2005, eight carrier families, with more than 1500 individuals of whom about 200 were affected, seven of Portuguese-Brazilian ancestry and one Afro-Brazilian, shared a founder haplotype with an estimated origin 23 generations ago (95% confidence interval: 13 to 39), consistent with the Portuguese colonisation of Brazil [92]. This finding is relevant to counselling Portuguese and Brazilian families with adult-onset motor neuron disease and dominant transmission.

None of the approved 5q SMA drugs has a mechanistic rationale or evidence in non-5q forms, which do not involve SMN1 or SMN2: nusinersen and risdiplam mechanisms are defined for chromosome 5q-related SMA with SMN deficiency, and onasemnogene abeparvovec is indicated only with biallelic SMN1 variants [21, 23, 28].

6.3. Respiratory failure with weakness in the infant: SMARD1 and main differentials

Congenital respiratory failure, present from birth, is not typical of SMARD1 and points towards 5q SMA type 0 or 1, congenital myotonic dystrophy type 1, early-onset myopathies, myopathy with areflexia, respiratory distress and dysphagia (EMARDD) and congenital myasthenic syndromes [4, 58]. The Oxford Desk Reference includes SMARD in the differential diagnosis of fetal akinesia and early-onset SMA and notes that it is heterogeneous and may be caused by IGHMBP2 variants [6, 53]. In the differential diagnosis of Charcot-Marie-Tooth disease, the same work includes the distal SMAs, a heterogeneous group of anterior horn degenerations with progressive distal weakness and atrophy, of which an autosomal recessive form has been mapped to 11q13, the IGHMBP2 region [97].

Sources: [4, 6, 46, 51, 54, 58, 60].

7. Treatment and Risk Management Strategies

7.1. General principles

5q SMA treatment combines SMN deficiency-targeting disease-modifying therapies with proactive multidisciplinary care stratified by functional status (nonsitter, sitter, walker), following the 2017/2018 international standards updating the 2007 consensus [42, 57, 98]. Treatment benefit is greatest before symptoms and decreases with disease duration because lost motor neurons cannot be recovered [64, 65, 99, 100]. No treatment restores motor neurons already lost [8].

7.2. Approved disease-modifying treatments

Sources: [19–30, 101–103].

7.3. Pivotal trial evidence

Nusinersen. In the phase 2 infantile-onset trial, treated infants acquired milestones including rolling and unsupported sitting [6, 104]. Phase 3 ENDEAR (121 infants with onset before 6 months) found motor milestone responses in 51% of treated patients versus 0% with sham, reduced death/permanent ventilation risk (hazard ratio 0.53) and death risk (hazard ratio 0.37), with greater benefit after shorter disease duration [64]. CHERISH (126 children with onset after 6 months) showed mean Hammersmith Functional Motor Scale-Expanded (HFMSE) change at 15 months of +4.0 with nusinersen versus −1.9 with sham (difference 5.9), and improvement ≥ 3 points in 57% versus 26% [105]. NURTURE treated 25 presymptomatic infants (15 with two and 10 with three SMN2 copies); all were alive without permanent ventilation after approximately 5 years. All with three copies achieved World Health Organization milestones; among the 15 with two copies, all sat unsupported, 14 walked with assistance and 13 independently [99, 106]. In 139 German adults with 5q SMA, mean HFMSE increased 1.73, 2.58 and 3.12 points at 6, 10 and 14 months without serious adverse events [107]. DEVOTE (part B), in infantile-onset patients with two SMN2 copies, showed high-dose Children's Hospital of Philadelphia Infant Test of Neuromuscular Disorders (CHOP-INTEND) change of +15.1 at day 183 versus −11.1 in a matched ENDEAR sham control (difference 26.2), with 58% versus 0% responders on Hammersmith Infant Neurological Examination section 2 (HINE-2) [19, 108].

Intravenous onasemnogene abeparvovec. In phase 1 START, all 15 type 1 infants were alive without permanent ventilation at 20 months versus 8% in a historical cohort; among 12 receiving high dose, 11 sat unsupported and 2 walked [101]. STR1VE-US (22 symptomatic infants with two copies) found 59% sitting for ≥ 30 seconds at 18 months (0 of 23 in natural history) and 91% surviving without permanent ventilation at 14 months (26% in natural history) [109]; STR1VE-EU found 44% sitting for ≥ 10 seconds and 97% surviving without permanent ventilation [110]. SPR1NT treated presymptomatic infants by 6 weeks: all 14 with two copies sat unsupported, all 15 with three stood independently, and 14 walked independently [100, 111]. A population study of 343 German, Austrian and Swiss patients found best motor outcomes with treatment before 6 weeks, three copies and presymptomatic status, less frequent hepatic adverse events up to 8 months, and no trajectory effect from prior SMN2-targeting treatment [65]. In a post-authorisation study of 24 children aged 1.5–9.1 years (8.5–21 kg), 21 had ALT above 3 times the upper limit of normal and 5 above 20 times, without bilirubin elevation, managed with prolonged corticosteroids [21]. The 2020 European ad hoc consensus made 11 recommendations on centre qualification, selection, safety and long-term monitoring [112]; a 2026 German, Austrian and Swiss Delphi consensus updated regional recommendations [113].

Intrathecal onasemnogene abeparvovec. Phase 3 STEER randomised 126 treatment-naïve patients aged 2–17 years who could sit but had never walked to Itvisma® (n = 75) or sham (n = 51). Mean HFMSE change at 48–52 weeks was +2.39 versus +0.51 (difference 1.88; 95% confidence interval: 0.51–3.25; p = 0.0074), with similar adverse event incidence; two treated and one sham patient had sensory symptoms [28, 114]. Phase 3b STRENGTH, involving 27 patients aged 2–17 years previously treated with nusinersen or risdiplam, recorded transient thrombocytopenia in 29.6%, hepatotoxicity in 14.8% and signs suggestive of dorsal root ganglion toxicity in 7.4% [115].

Risdiplam. FIREFISH part 1 found that 0.2 mg/kg/day doubled blood SMN protein [116]; part 2, in 41 type 1 infants with two copies, found 29% sitting unsupported for 5 seconds at 12 months and 85% surviving without permanent ventilation versus the 42% upper natural history bound [117]. SUNFISH part 2 (180 nonambulatory type 2 or 3 patients aged 2–25 years) showed a 1.36-point improvement in the 32-item Motor Function Measure with risdiplam versus a 0.19-point decline with placebo (difference 1.55; p = 0.016), with stabilisation in older patients [118]. RAINBOWFISH treated 26 presymptomatic infants between birth and 42 days: at 12 months, 81% sat unsupported, 54% stood and 42% walked independently; all 23 completing 24 months were alive without permanent ventilation or feeding support [119].

Apitegromab. Phase 3 SAPPHIRE enrolled 188 nonambulatory type 2 or 3 patients aged 2–21 years receiving nusinersen or risdiplam, randomised to apitegromab or placebo every 4 weeks. Among those aged 2–12 years, the 12-month HFMSE difference was 1.8 points (p = 0.019) for combined doses, nonsignificant for 20 mg/kg alone [103].

7.4. Combined and sequential therapies

Combination or sequencing is used when response is considered insufficient. Phase 4 RESPOND treated 37 children up to 36 months with suboptimal status after onasemnogene abeparvovec (92% with two SMN2 copies) with nusinersen. At day 302, HINE-2 and CHOP-INTEND improved, independent sitting was acquired, NfL rapidly decreased and CMAP increased, without new safety signals [41]. A 2025 systematic review identified 19 studies and 6 ongoing trials, with 29 combination-treated patients (26 dual, 3 triple), no consistent additive toxicity evidence, but undetermined long-term efficacy and optimal sequence [120]. Apitegromab is currently the only treatment approved (in the US) specifically as an adjunct to SMN2-targeting therapy [30].

7.5. Investigational treatments

Developing myostatin-pathway inhibitors include taldefgrobep alfa, evaluated as an adjunct in phase 3 RESILIENT (NCT05337553; 269 participants), which according to the sponsor missed its primary endpoint (48-week MFM-32 change) in the overall population, showing a favourable difference only in subgroup analysis, without an SMA authorisation application [121, 122]. Antimyostatin antibody RO7204239 (GYM329) is being evaluated with risdiplam in phase 2/3 MANATEE (NCT05115110; 97 participants; primary completion anticipated in late 2026) [123]. Reldesemtiv, a fast troponin complex activator, was studied in phase 2 types 2–4 [8]. Fetal treatment is investigational: intra-amniotic antisense oligonucleotides and cordocentesis-administered gene therapy have been tested in animals; one case of maternal third-trimester risdiplam followed by postnatal treatment reported normal motor function at two years [80, 124].

7.6. Multidisciplinary care (2017/2018 standards and updates)

The following table summarises international care recommendations stratified by functional status, supplemented by the Oxford Desk Reference and Síndromes Genéticas: Reconhecer para Tratar.

Sources: [6–8, 42, 57, 59, 98].

The Oxford Desk Reference notes that type 1 infants traditionally received palliative care; Bach and colleagues (2000) demonstrated prolonged survival with noninvasive ventilation, feeding support and physiotherapy without neuromuscular improvement. For type 2, it highlights specialist physiotherapy and adapted sitting, feeding and aspiration problems, progressive respiratory failure worsened by scoliosis and scoliosis surveillance to preserve respiratory function [6]. Síndromes Genéticas: Reconhecer para Tratar adds routine influenza, pneumococcal and respiratory syncytial virus immunisation; sleep-time noninvasive ventilation with sleep disturbances and daytime hypercapnia; assisted cough and postural drainage; tracheostomy with mechanical ventilation for ventilatory failure; nasogastric feeding or gastrostomy; food thickening; vitamin D and calcium; external supportive devices for patients with minimal standing capacity; and encouragement of sport [7]. In the disease-modifying era, the 2026 hip dislocation Delphi consensus updated radiological surveillance and intervention [59], while the 2026 Latin American consensus proposed function-stratified multidisciplinary care and treatment response assessment adapted to unequal access [125].

7.7. Adverse effect management

Post-lumbar puncture syndrome with nusinersen is managed with recumbency, hydration and analgesia; in patients with severe scoliosis or spinal fusion, lumbar puncture may require computed tomography guidance [19, 126]. Proteinuria above 0.2 g/L warrants repeat testing and further evaluation, and thrombocytopenia requires a platelet count before each administration [19]. With onasemnogene abeparvovec, immune-mediated hepatotoxicity requires prolongation or increase of corticosteroid therapy and, if aminotransferases remain above 2 times the upper limit of normal after 30 days, referral to paediatric gastroenterology or hepatology; corticosteroid therapy must never be stopped abruptly [21]. Thrombotic microangiopathy (thrombocytopenia, haemolytic anaemia, acute kidney injury) requires immediate assessment by haematology and nephrology [21, 28]. With risdiplam, counselling on the reproductive risks identified in animal studies (embryofetal toxicity, effects on male fertility) and monitoring of interactions with MATE transporter substrates are part of prescribing [23]. With apitegromab, caution is recommended in patients with low bone mineral density or multiple fractures, and the benefit-risk balance should be reassessed after a fracture [30]. The French PNDS reports, in addition to post-lumbar puncture syndrome, cases of hydrocephalus with nusinersen [1].

7.8. Comparative regulatory status, pivotal trials and evidence hierarchy

These data have differing evidential strength: peer-reviewed trials underpin the evidence; sponsor-reported results without full publication are preliminary; a positive CHMP opinion is a recommendation, with authorisation granted only by European Commission decision; and authorisation guarantees neither marketing, reimbursement nor national access, which depend on INFARMED assessment in Portugal and ANVISA registration and, for the SUS, CONITEC assessment in Brazil [20, 22, 24, 29].

In Brazil, a 2026 description of patients at nine SUS referral centres reports public availability of nusinersen and risdiplam for types 1 and 2 and onasemnogene abeparvovec for type 1 in the first 6 months. Type 3 patients lack SUS disease-modifying treatment access and use judicial routes or private care [127]. In Portugal, European authorisation applies directly, while actual access depends on assessment and hospital funding for each medicine.

Sources: [64, 103, 105, 109, 114, 117, 118, 122].

These trials cannot rank treatments by indirect comparison. Designs differ (sham- or placebo-controlled versus single-arm studies compared with natural history), as do populations (age and disease duration at treatment, SMN2 copies, symptomatic or presymptomatic status) and endpoints (binary milestones, HFMSE, MFM-32, ventilation-free survival). HFMSE or MFM-32 differences of 1.5–2 points are population averages in established disease, primarily representing stabilisation in absolute terms rather than individual response. Presymptomatic findings (NURTURE, SPR1NT, RAINBOWFISH) come from small open-label cohorts without concurrent controls [99, 100, 111, 119]. Negative or partially negative trials (RESILIENT; SAPPHIRE 20 mg/kg dose) are part of the evidence and show that myostatin inhibition does not produce a uniform effect [103, 122].

Evidence extrapolation and off-label use should be distinguished. Treating a presymptomatic infant with 4 SMN2 copies follows 2020 recommendations [78], but intravenous onasemnogene abeparvovec is outside the European indication (up to 3 copies or type 1) and within the US indication (under 2 years); above 2 years, the same drug is off-label in the US. Combined or sequential treatment (Section 7.4), prenatal treatment (Section 7.5) and any use in non-5q forms are off-label; the first two rely on extrapolation from open-label studies and case reports [41, 120, 124]. In pregnancy, the risdiplam label advises against exposure on the basis of animal data [23].

7.9. SMARD1: supportive care and investigational therapies

There is no approved disease-modifying therapy for SMARD1 in the EU or the US, and 5q SMA drugs have no mechanistic basis or indication in this disease; treatment is supportive [3, 4, 43]. The decision on ventilatory support is the first intervention and often has to be taken before genetic confirmation, because respiratory failure is life-threatening; mean survival without artificial ventilation is around 9 months [4]. Invasive home ventilation via tracheostomy is the usual form of long-term support in the published series; in the three patients of Leśniak and colleagues, tracheostomy was performed at 4, 6 and 13 months [3, 47]. Gastrostomy, alone or with jejunal extension, is necessary when dysphagia and gastroparesis prevent safe oral feeding [3]. Daily physiotherapy, orthoses for equinovarus foot and braces for scoliosis are part of treatment [3]. Autonomic dysfunction requires monitoring of bladder function, with catheterisation in patients with retention and assessment of reflux and renal function, and monitoring of heart rhythm and blood pressure [4, 61]. The main causes of death are respiratory failure, complications of ventilation (sepsis, pneumonia) and progressive autonomic dysfunction [3, 4]. The decision to start or limit ventilation should be shared with the family, with information on the course described in the cohorts: stabilisation after 2 years, school integration of two thirds of ventilated patients in the Berlin series and absence of walking [47, 63].

Research on targeted therapies is mainly at the preclinical stage. In the nmd mouse, systemic administration of AAV9-IGHMBP2 restored the protein and increased survival by 450%, with motor and neuromuscular improvement [128]; low-dose intracerebroventricular injection of single-stranded AAV9-IGHMBP2 had dose-dependent efficacy, and the authors warned of the potential effects of high doses [129]; and, in 2026, a comparison of two optimised AAV9 vectors showed greater long-term efficacy and a better safety profile with the MECP2-derived P546 promoter than with the chicken beta-actin promoter [130]. These results are preclinical and do not establish human efficacy or safety.

Sources: [131, 132].

Both programmes are early-phase human studies, without published efficacy results; the oligonucleotide VCA-894A targets a single variant of one patient with CMT2S and cannot be extrapolated to patients with other variants. Outside these studies, there is no drug with an established dose for SMARD1.

7.10. Recommendations of the French PNDS (HAS, 2021)

Organisation and therapeutic decision. The PNDS defines a team coordinated by a reference paediatrician or neurologist in a reference or competence centre for neuromuscular diseases, with paediatric neurology or neurology, physical and rehabilitation medicine, pulmonology, orthopaedics, stomatology and orthodontics, gastroenterology, otorhinolaryngology, anaesthesia and intensive care, clinical genetics, orthotics and prosthetics, physiotherapy, occupational therapy, speech and language therapy, psychomotor therapy, psychology, dietetics, orthoptics, nursing, podiatry, school and home assistants, ventilation and enteral nutrition providers and patient associations; rehabilitation services, hospital-at-home and mobile palliative care teams may be involved [1]. Follow-up is mainly clinical and includes, in children, weight, height, head circumference and chest circumference at nipple level [1]. In France, the indications for innovative therapies and their follow-up are decided in national multidisciplinary consultation meetings under the aegis of FILNEMUS, one paediatric and one for adults; withholding treatment may be discussed, collegially and case by case, in the presence of severe type 1 at diagnosis, a difficult route of administration (severe scoliosis or spinal fusion) or lack of response in the medium or long term [1]. The objectives defined by the PNDS are motor improvement or stabilisation of weakness, improvement, stabilisation or slowing of respiratory deterioration and delay or avoidance of assisted ventilation [1]. The PNDS nusinersen regimen (12 mg intrathecally on days 0, 14, 28 and 63 and then every 4 months, regardless of age) matches the European SmPC for the 12 mg regimen; the PNDS predates the high-dose regimen and the European authorisations of risdiplam and of the intrathecal formulation of onasemnogene abeparvovec, and described risdiplam and intravenous onasemnogene abeparvovec as available in France under temporary authorisation for use (ATU) (sections 7.2 and 7.8) [1, 19, 20]. The PNDS cites NURTURE with a mean follow-up of 34.8 months (all patients sitting and 88% walking independently), the French cohort of 123 children treated with nusinersen for 1 year (34 with type 1 and 89 with type 2), with significant improvement in HINE-2 below 2 years of age, greater use of nutritional and respiratory support in type 1 below 2 years (non-significant difference) and improvement in axial, proximal and distal motor items above 2 years without acquisition of walking, and observational studies in adults aged 16 to 65 years with types 2 and 3, with improvement in HFMSE and the 6-minute walk test awaiting controlled confirmation [1]. In spinal fusion, the PNDS suggests leaving one or two lumbar levels unfused to allow intrathecal injections, a practice without published studies [1].

Early type 1 without an indication for innovative therapy. The PNDS describes comfort care for children whose severity at diagnosis does not justify innovative therapies [1]. Respiratory care: manual airway clearance by a physiotherapist, with nasopharyngeal suctioning several times a week, including preventive suctioning, and training of parents in home suctioning; positive-pressure airway clearance devices are poorly suited to small infants, owing to lack of cooperation, fatigability and bulbar instability; early antibiotic therapy in the event of infection or congestion, without evidence for continuous antibiotic prophylaxis; up-to-date vaccination (Haemophilus, pertussis, pneumococcus, influenza); palivizumab discussed but not systematic; low-flow oxygen to avoid hypercapnia, in hospital during decompensations and at home at the end of life; non-invasive ventilation case by case to overcome an acute episode, useless and contraindicated in bulbar dysfunction (used in 7% of cases in the palliative setting in France); and long-term invasive ventilation via tracheostomy considered not appropriate in severe forms of type 1, a position the PNDS presents as internationally consensual [1]. Digestive care: adaptation of textures and thickening of liquids, nasogastric tube as a complement to or substitute for oral feeding, gastrostomy rare in the palliative setting in France (about 3.4%), transdermal scopolamine for hypersalivation and contraindication of botulinum toxin, which would worsen bulbar denervation [1]. The lying position (supine or lateral) is the best tolerated as the disease progresses, because it spares the diaphragm; discomfort (intermittent and then almost continuous moaning) is treated with changes of position and with amitriptyline and/or opioids, given the poor efficacy of paracetamol; dyspnoea and fear of suffocation are treated with midazolam or another benzodiazepine (bromazepam, alprazolam), with or without oral morphine; the oral route is preferred, with the rectal route (midazolam) in ileus; end of life should be planned early, with advance directives where possible (in one study, half of parents preferred death at home), and opioids require bowel regulation and monitoring for urinary retention [1].

Rehabilitation and orthopaedics. Motor scales (CHOP-INTEND, Hammersmith Functional Motor Scale, Upper Limb Module and its revised version, Motor Function Measure, HINE and timed tests, including the 6-minute walk test) are applied annually or more frequently when a therapy is being discussed; in adults, the MFM-32, ABILHAND-NMD, ACTIVLIM, Functional Independence Measure and RULM are used [1]. Recommended individual physiotherapy sessions last 30 minutes, 1 to 5 sessions per week, on land or in hydrotherapy, with massage, passive and active-assisted mobilisation and stretching targeting typical contractures (hip flexors, external rotators and adductors; hamstrings; triceps surae and tibialis posterior; biceps, flexor carpi ulnaris, pronator teres and flexor digitorum profundus; splenius capitis) [1]. Exercise should be aerobic (below 70% of maximum heart rate), concentric, of moderate or low intensity in the distal muscles and isometric in the trunk and neck, painless and supervised by professionals: hydrotherapy, hippotherapy and concentric and eccentric exercises in patients who sit; walking, cycling, swimming, hippotherapy, yoga and elliptical training in ambulant patients; in adult type 3, concentric aerobic programmes 3 times a week, with progressive intensity, for at least 12 weeks, of demonstrated feasibility but unvalidated efficacy [1]. Ankle-foot orthoses against equinus and varus are almost systematic, knee-ankle-foot orthoses are feasible in young children without major contractures, and wrist and hand orthoses are used mainly at night; the seating brace with tray is proposed at the theoretical age of sitting acquisition, and the Garches brace (corset garchois), preferred by French recommendations because it controls scoliosis while respecting respiratory function, can be started from 1 year, often with head support and chin rest; braces are not usually used in ambulant patients [1]. Standing can begin between 18 months and 2 years, at least 1 hour 3 times a week and ideally 1 hour a day, and a powered wheelchair can be used from 18 months to 2 years if attention and cognition allow; technical aids include arm supports and exoskeletons, grasping and feeding aids, home and vehicle adaptation and assistance dogs [1].

Scoliosis with a Cobb angle greater than 20° should be monitored every 6 months until skeletal maturity and annually thereafter; the PNDS decision tree proposes clinical monitoring below 15–20°, bracing and monitoring above 15–20° and surgical discussion above 50°, and the decision to instrument is based on a main curve angle greater than 40–50° or progression greater than 10° per year, weighing loss of trunk control without a brace after maturity, respiratory deterioration, rib deformity, hyperkyphosis, poor brace tolerance and pelvic obliquity [1]. Below 8–10 years, growing rods without fusion are used (mean age at placement 7 to 8 years, not before 5 years), with lengthenings every 2 to 3 years in the minimally invasive techniques developed in France, or magnetic (MAGEC) or self-expanding (NEMOST) rods to reduce reoperations; the VEPTR system is no longer recommended; in mature patients posterior spinal fusion is performed, with or without extension to the pelvis, and severe rigid deformities may be prepared with distraction casts or halo-gravity traction [1]. Hip instability should only be operated on in the presence of significant and persistent pain, because operated hips tend to redislocate; fractures are treated with casting in non-ambulant patients, avoiding immobilisation longer than 4 weeks, and with surgical stabilisation for fractures of the long bones of the lower limbs in ambulant patients and for femoral neck fractures in non-ambulant patients; the first densitometry (DXA) is usually performed at the first spontaneous fracture or in the presence of diffuse pain on handling, and bisphosphonates are considered for spontaneous fractures due to osteopenia [1].

Respiratory. Respiratory assessment looks for signs of aspiration, nocturnal cough and nocturnal hypercapnia, recurrent infections, weight faltering, paradoxical breathing, the quality of cry, voice and cough and, in infants, the ratio of chest circumference to head circumference [1]. In infants, monitoring is by capillary blood gas and nocturnal or nap-time oxycapnography, at a frequency dictated by severity; in children, annually or six-monthly, with spirometry (forced vital capacity better supine than sitting, reliable from 4 or 5 years), sniff nasal inspiratory pressure (SNIP), maximal inspiratory and expiratory pressures and peak flow; capillary blood gas is indicated if forced vital capacity is below 60% or there are signs of hypoventilation, and home oxycapnography or polysomnography diagnoses sleep hypoventilation [1]. Spinal radiography serves as the annual pulmonary check, to limit irradiation; chest computed tomography is reserved for suspected bronchial compression, a chronic focus or bronchiectasis; in type 3, investigations are performed only in the presence of signs; pulmonary function tests are systematic before surgery, and fitting a brace requires spirometry with and without the brace [1]. In types 1C and 2, non-invasive ventilation should be preventive, to promote lung and chest growth and reduce pneumonia and atelectasis, and may be guided by polysomnography; long-term continuous positive airway pressure is not recommended; hyperinsufflation (with a ventilator or pressure relaxator) is proposed from 2 years, 3 to 5 sessions per week or daily, for 15 to 20 minutes, supine with an abdominal binder, in the absence of significant bulbar dysfunction; mechanical insufflation-exsufflation can be started from 1 year; intrapulmonary percussion complements airway clearance and can be performed by parents; tracheostomy is discussed case by case; mucolytics are contraindicated and nebulised hypertonic saline requires great caution [1]. Influenza vaccine should be given annually from 1 year of age, pneumococcal vaccination follows the recommendations for chronic respiratory failure, and palivizumab may be given during the respiratory syncytial virus season in the first two years, especially in children in group settings; in type 3, vaccination indications are those of type 2 [1]. The European SmPC for palivizumab sets 15 mg/kg intramuscularly, once a month during the risk season, with no maximum dose per administration defined, and its indications (prematurity, bronchopulmonary dysplasia, haemodynamically significant congenital heart disease) do not include SMA, so the PNDS recommendation is an off-label extension [133].

Digestive and nutrition. Assessment is clinical (looking for aspiration and food selection, highly suggestive of aspiration in a child with SMA, observation of swallowing, abdominal palpation and growth, without specific charts); upper gastrointestinal contrast study and endoscopy are performed case by case, and DXA, vitamin D, serum calcium and the urinary calcium/creatinine ratio according to the clinical picture [1]. In early type 1, the nasogastric tube (or, rarely, nasojejunal) is the first option and gastrostomy is rare in France (3%), unlike other countries, which combine early gastrostomy and Nissen fundoplication; reflux is treated with proton pump inhibitors and mucosal protectants, and prokinetics (domperidone, metoclopramide) are not used because of cardiac risk [1]. In types 1C and 2, severe undernutrition despite adequate caloric intake should lead to consideration of nocturnal non-invasive ventilation, even with normal polysomnography; constipation is a priority (fibre, hydration, abdominal massage, regular toilet visits to take advantage of the gastrocolic reflex, laxatives); acute gastroparesis, almost always accompanied by metabolic decompensation, is treated with pyridostigmine and intravenous fluids (the PNDS intravenous dose, identical to the oral dose, is discussed in the following table), and chronic gastroparesis with anticholinesterases, with erythromycin as second line; metabolic decompensations (acidosis or ketoacidosis) are treated with hydration, glucose infusion and avoidance of fasting; superior mesenteric artery syndrome is treated with refeeding, parenteral in very severe cases; in extreme cases of gastroparesis a duodenal tube may be used; in type 3 it is sufficient to monitor nutritional status and bowel transit [1].

Emergencies. The PNDS identifies four urgent situations: respiratory congestion, acute respiratory decompensation, acute gastric dilatation and subacute pain syndrome due to osteoporosis [1]. Hypoxia is confirmed by a saturation below 94%; if manual cough assistance is insufficient, mechanical insufflation-exsufflation is used with inspiratory and expiratory pressures of 30 cmH2O, in 4 series of 5 cycles separated by 30-second pauses with suctioning of secretions, up to one session every 2 hours if tolerated; antibiotic therapy is decided according to infectious status and duration of congestion; non-invasive ventilation is started in the presence of hypoxia, hypercapnia, respiratory fatigue or inability to speak, and conventional ventilation is reserved for contraindication to non-invasive ventilation (severe swallowing disorders), deterioration despite it or a previously tracheostomised child [1]. In acute gastric dilatation, plain abdominal radiography shows marked gastric distension and biochemistry shows metabolic acidosis with hypoglycaemia; if oral hydration fails after 1 hour, urgent intravenous hydration is indicated, and the prone position may reduce vomiting [1]. The diffuse bone pain of osteoporosis, which can severely disturb sleep and general condition, usually responds to intravenous bisphosphonates (following table) [1].

Anaesthesia. No anaesthetic technique is formally contraindicated, but anaesthesia should be prepared by anaesthetists experienced in neuromuscular diseases [1]. Mask anaesthesia is used for minor surgery; intubation may be difficult owing to limited mouth opening or neck stiffness and require videolaryngoscopy or fibreoptic intubation; pre- or postoperative tracheostomy is discussed case by case in major surgery; intra- and postoperative ventilatory support is frequent, and transition to non-invasive ventilation after early extubation is recommended [1]. Suxamethonium should be avoided, as in all neuromuscular diseases, because of the risk of hyperkalaemia, although no adverse effects have been described in SMA; non-depolarising neuromuscular blockers may have a prolonged effect, so short half-life agents with neuromuscular monitoring are preferred and intubation without neuromuscular blockade should be considered; halogenated agents can be used, with no cases of malignant hyperthermia described in SMA; short-acting opioids are well tolerated if titrated and monitored, and finger weakness may prevent patient-controlled analgesia; regional anaesthesia is possible, but severe or operated scoliosis may prevent neuraxial anaesthesia; preoperative echocardiography is not systematic outside types 0 and 1, in which congenital heart disease occurs [1].

Pregnancy. Delivery should take place in a level 2 or 3 maternity unit; the preconception consultation, ideally multidisciplinary and with pulmonary function tests, assesses the course over the previous 5 years, starts high-dose folic acid and vitamin D if necessary and prepares the home and aids; genetic counselling is systematic [1]. In the first trimester, thromboprophylaxis is discussed, especially in women using a wheelchair, and teratogenic drugs are reviewed; reflux may be treated in the second trimester; physical activity and weight control are part of follow-up; respiratory monitoring is quarterly, with clinical examination, forced vital capacity, inspiratory pressure, cough function and blood gases [1]. Pregnant women with forced vital capacity below 50% of predicted (or below 1 litre), maximal inspiratory pressure below 60 cmH2O or peak flow below 160 L/min are defined as high risk and require blood gases and sleep recording; with a vital capacity below 20%, the risk of decompensation is high, especially in the second trimester, with cases of hypercapnic coma at 25 weeks requiring intubation and delivery [1]. In neuromuscular diseases in general, a vital capacity below 1 litre contraindicates pregnancy, and hypoxaemia below 85% is associated with fetal survival of only 12%, but the contraindication is not absolute in SMA, with successful pregnancies described with a vital capacity of 11% of predicted [1]. The current trend is to plan caesarean section; early epidural analgesia with low-dose opioids is preferred, with regional or general anaesthesia decided case by case, continuous capnography and maintenance of prior ventilation; the risk of aspiration pneumonia increases in the third trimester, as does that of respiratory difficulty during the expulsive phase; in the postpartum period, fever, feeding difficulties, depression and hormonal changes may prolong the worsening [1].

Dentistry, urology and endocrinology. The PNDS recommends regular dental surveillance from early childhood (caries, occlusion, maxillary growth), taking into account masticatory weakness, temporomandibular joint contractures, brushing difficulties and midface flattening due to ventilation mask pressure; treatment of reflux protects the enamel [1]. Urinary retention is treated with catheterisation and incontinence with beta agonists; hormonal contraception may be considered in girls [1].

Sources: [1, 133–136].

7.11. Divergences between the French PNDS and the other sources

Guideline doses and intervals are the reference and labels serve for comparison; the following divergences result mainly from the date of the PNDS (2020 text), the population it addresses and the source of the epidemiological values.

Sources: [1, 4, 6–8, 10, 19, 20, 31, 34, 42, 45, 57, 66, 74–76, 141].

8. Reproductive Options and Family Counselling

8.1. Recurrence risk

5q SMA is autosomal recessive; approximately 98% of patients' parents are heterozygous carriers, giving each sibling a 25% affected risk and 50% asymptomatic carrier risk [7]. A de novo deletion in one allele occurs in approximately 1.7%–2% of patients, making testing of both parents essential: results modify recurrence counselling and other relatives' testing [6, 8]. When a parent has two SMN1 copies and an affected child, possibilities include [2+0], an intragenic variant in a single-copy allele, de novo mutation and rarely germline mosaicism [8, 81]. SMA type is usually concordant within a sibship, with some variability, but any type may occur in other family branches. For example, an uncle of a child who died with type 1, without consanguinity or partner family history, has an affected-child risk of 1/2 × 1/50 × 1/4 = 1/400 [6]. Rare asymptomatic individuals with homozygous SMN1 absence, usually patients' siblings, reflect SMN2 copies and other modifiers and may later develop mild disease [6, 8].

8.2. Carrier testing and silent [2+0] carriers

Most carriers have one SMN1 copy ([1+0]); some have two copies on one chromosome 5 and none on the other ([2+0]), indistinguishable from noncarriers by dosage [6, 81]. Ogino and colleagues found three or four SMN1 copies in approximately 7% without family history, indicating a relatively frequent two-copy allele (approximately 3.3% of alleles) [6, 81]. Two-copy chromosome frequency varies across populations: Hendrickson and colleagues found multicopy SMN1 alleles in 27% of African Americans versus 3.3%–8.1% in other groups, reducing dosage-based detection in African ancestry populations [142]. Sugarman's pan-ethnic laboratory series of 68,471 individuals showed an a priori carrier frequency of 1/54 and detection rate 91.2%, ranging from 1/47 with 94.8% detection in White individuals to 1/72 with 70.5% in African Americans [10]. Common carrier and noncarrier genotypes are illustrated in Verhaart and colleagues' open-access figure (https://pmc.ncbi.nlm.nih.gov/articles/PMC5496354/figure/Fig1/) [11].

The Oxford Desk Reference quantifies the residual risk: an individual from the general population with two SMN1 copies has a residual probability of being a carrier of 1/820; in an unaffected sibling of a patient with a homozygous deletion, two copies reduce the risk from 2/3 to 1/13, which becomes negligible if both parents are known to be carriers of a single copy [6]. The residual risk can be reduced by testing for variants associated with duplicated alleles, such as the g.27134T>G variant in intron 7 of SMN1 (published genomic designation, relative to the genomic sequence of the gene), identified by Luo and colleagues (2014) on a specific haplotype of duplication alleles in Ashkenazi Jews and present in other ethnic groups [143]. Dosage does not detect intragenic variants, which account for about 2% of pathogenic alleles [6, 8].

8.3. Population carrier screening

The American College of Medical Genetics and Genomics (ACMG) recommended pan-ethnic SMA carrier screening in 2008 [144]; the American College of Obstetricians and Gynecologists (ACOG) recommended offering it to all pregnant women or women planning pregnancy in 2017 [145]; and ACMG's 2021 recommendation included SMA among tier 3 disorders offered to all pregnant individuals and reproductive-age couples [146]. The Oxford Desk Reference includes SMA in its carrier-testing table at frequency 1/50, testing SMN1 exon 7 deletion in at-risk relatives and the general population [141]. Cascade screening should be offered to relatives, particularly with consanguinity [6].

8.4. Reproductive options

Couples in whom both partners carry a variant may choose prenatal diagnosis by chorionic villus sampling at 11 weeks (or amniocentesis), with SMN2 copy-number determination in affected fetuses; preimplantation genetic testing (PGT-M) after in vitro fertilisation, described for type 1 since 1999; donor gametes; or adoption [6, 7, 80]. In the disease-modifying era, counselling about continuing an affected pregnancy should include presymptomatic treatment outcomes, their dependence on SMN2 copies, chronic treatment burdens and long-term uncertainty [78, 80]. Affected individuals' risk of having affected children depends on the partner's carrier status, which should be tested [8]. Pregnancy requires prior respiratory and anaesthetic assessment and consideration of drug safety: the risdiplam label advises against pregnancy exposure based on animals and maintains a pregnancy registry [6, 23].

8.5. Asymptomatic relatives

Asymptomatic younger siblings should have genetic status determined immediately to allow presymptomatic treatment [8]. After positive newborn screening, genetic counselling should be offered when communicating the result and include parental testing [31].

8.6. Counselling in SMARD1 and other IGHMBP2-related diseases

SMARD1 is transmitted in an autosomal recessive manner: the parents of a patient are, as a rule, asymptomatic heterozygous carriers, and each sibling has a 25% risk of being affected, 50% of being a carrier and 25% of inheriting neither variant [44, 45]. After identification of both variants and confirmation of phase by segregation, cascade testing of relatives, prenatal diagnosis by chorionic villus sampling or amniocentesis and preimplantation genetic diagnosis can be offered; the request for prenatal diagnosis was one of the reasons given by Grohmann and colleagues for defining clear clinical criteria [3, 45]. If only one variant is known, prenatal diagnosis is not reliable, which reinforces the search for deletions, duplications and deep intronic variants in the index case [48, 49]. Expressivity varies within the same sibship: the twin girls from a triplet pregnancy with the same variants had symptom onset at 4 and 11 months and a different course, and the healthy triplet brother was a carrier of one of the variants [3]. The correlation between variant type and phenotype (SMARD1 or CMT2S) is indicative but does not allow the phenotype of a new combination to be predicted reliably [51, 52]. In consanguineous couples with a child who died of unexplained sudden infant death, study of IGHMBP2 may identify the risk of recurrence [45]. In X-linked SMARD2, the risk depends on the mother's carrier status; in the index case described, the variant arose de novo [54].

8.7. Communication of the diagnosis and family support

The French PNDS recommends that communication of the diagnosis be prepared and carried out by an experienced physician in a reference or competence centre, with time and benevolent neutrality: it should state the diagnosis, the severity and the expected course according to natural history and be linked to a care plan, with discussion of therapeutic options with the parents and with other professionals, including the committee for the evaluation of innovative therapies [1]. Closely spaced consultations are proposed to divide the information, explanation to the child in age-appropriate words and psychological support for the family, including siblings, from diagnosis onwards [1]. Given the carrier frequency in the general population, the PNDS recommends a genetic counselling consultation for the relatives of a patient, before any pregnancy, with information on prenatal diagnosis, preimplantation genetic diagnosis and adoption [1]. In an Australian study cited by the PNDS, parents described the diagnosis as traumatic, with feelings of loss and helplessness, but also a sense of responsibility and regained control when making decisions about the life and death of their child, which underpins advance care planning [1].

9. Special Considerations: Population Diversity and Epidemiology

9.1. Population-specific carrier frequency and incidence

Verhaart and colleagues emphasise that most prevalence and incidence studies are old, clinically diagnosed and limited to European populations. Carrier frequencies do not translate directly into incidence because extreme phenotypes (in utero death, asymptomatic adults) have unknown frequency [11]. The Oxford Desk Reference population table derives from pan-ethnic screening of 23,453 individuals, where SMA ranked among the ten highest carrier-frequency diseases in every population, highest in Southern Europe (1/40.3) [141]. Lower carrier frequency and detection in sub-Saharan ancestry populations partly reflect more alleles with two or more SMN1 copies, making dosage screening less informative [10, 142]. Incidence is higher where consanguinity is frequent [8].

9.2. Newborn screening data

Newborn screening produced the first genotype-based incidence estimates: 1 in 14,694 in the US (2018–2022) [66]; 1:14,515–1:15,520 in Portugal's 100,000-newborn pilot (2022–2024), and 10 cases among 87,708 newborns in the first national programme year (2025) [74, 75, 77]. These are minimum estimates because screening misses approximately 5% of compound heterozygous patients with a point variant [32, 66]. A 2026 cost-effectiveness analysis for Spain, Greece and Portugal estimated that screening identifies and treats 86% of Portuguese patients early each year, with cost savings and quality-adjusted life-year gains compared with clinical diagnosis [147].

9.3. Portugal, Brazil and Portuguese-speaking countries

Beyond newborn screening data, Portugal has no published genotype-based national SMA prevalence study; Pires and colleagues' descriptive 2011 series, cited in Síndromes Genéticas: Reconhecer para Tratar, is a hospital case registry [7]. A 2026 Latin American consensus of 40 experts from 15 countries found 90% reporting MLPA access, but only 35% through public systems; no country had national SMA newborn screening (22.5% reported pilots or proposals), 92.5% reported access to at least one disease-modifying therapy, and diagnosis-to-treatment delays were frequent [125]. Brazil's Law No. 14.154/2021 provides phased national screening expansion including 5q SMA. Two screening studies supplied initial genotype-based incidence estimates: the São Paulo State pilot found 14 cases among 194,714 newborns (1:13,908; 95% CI: 1:8289–1:25,440) [148]; a multicentre study using samples from Rio Grande do Sul, São Paulo, Mato Grosso and Bahia found 7 among approximately 80,000 (1:11,428), an estimate the authors considered imprecise because of short sampling duration [149]. These measure homozygous SMN1 exon 7 absence and are minimum estimates. The description of 155 type 2 and 3 patients from nine SUS referral centres characterises clinical profiles and diagnostic delay rather than prevalence [127]. Brazil's VAPB p.(Pro56Ser) founder variant causes adult-onset SMA and ALS attributed to Portuguese colonisation, relevant in Portuguese–Brazilian families [92]. No published 5q SMA incidence or carrier-frequency data were identified for Angola, Mozambique, Cape Verde, Guinea-Bissau, São Tomé and Príncipe or Timor-Leste; extrapolation from other sub-Saharan populations is unvalidated [11].

9.4. Other populations and treatment access

Screening-based incidence data are scarce in Africa, the Middle East and South Asia, where estimates derive from carrier studies [11]. Disease-modifying treatment access varies between regions and within countries according to costs, reimbursement and newborn screening [32, 125]. STEER and STRENGTH included Asian, South African, Latin American and European populations (59% of STEER patients were Asian), broadening representation in intrathecal efficacy data [28, 114].

9.5. Epidemiology of SMARD1

The exact prevalence of SMARD1 is unknown. Orphanet gives a prevalence below 1/1,000,000; Saladini and colleagues report that diaphragmatic paralysis occurs in about 1% of patients with early-onset SMA and cite an estimated incidence of 1/100,000 [2–4]. The two measures do not necessarily contradict each other, because early mortality reduces prevalence relative to incidence, but neither comes from a population-based study. By 2024 about 150 patients had been described, mainly in European series (Germany, France, United Kingdom, Poland, Turkey) and in small Asian series [3, 47, 49, 50, 52, 63]. In China, a series of three patients suggested the c.1060G>A p.(Gly354Ser) variant as a possible recurrent variant [50]. The sources consulted do not describe series from Portugal or Brazil, which does not demonstrate the absence of patients in those countries. As SMARD1 is not detected by newborn screening for SMA, its frequency remains dependent on clinical diagnosis and sequencing [3]. The relevant European reference network is ERN EURO-NMD, and TREAT-NMD brings together resources for rare neuromuscular diseases [5, 150].

9.6. France: epidemiology, organisation of care and social rights

The French PNDS estimates an incidence of 1/6000 births, about 120 to 124 new cases per year in France, and carrier frequencies of 1/40 in France, 1/50 in the US, 1/60 in Asia and 1/70 in Africa; these values are estimates predating newborn screening and were not obtained by population genotyping (section 7.11) [1]. Care is organised in the FILNEMUS health network (filière) for neuromuscular diseases, with three multisite reference centres — PACA-Réunion-Rhône-Alpes (coordinated in Marseille), Nord/Est/Île-de-France (coordinated in Garches) and Atlantique-Occitanie-Caraïbe (coordinated in Bordeaux) — and a network of competence centres that includes the overseas departments [1]. SMA is recognised as a long-term condition (ALD) by the social security system [1]. National and international registries serve to measure epidemiology, prognostic factors, criteria for starting and stopping innovative therapies and their efficacy and tolerability [1].

The PNDS describes the social pathway by age: in early childhood, care in a crèche or by a childminder, rehabilitation in an early medico-social action centre (CAMSP) or in private practice, a file with the Maison départementale des personnes handicapées (MDPH) for the disability rate, the education allowance for a disabled child (AEEH) and its supplements, the mobility-inclusion card and parental leave (AJPP); at school age, an individualised reception plan (PAI), a personalised schooling plan (PPS) with a support assistant (AESH), adapted school transport, a special education and home care service (SESSAD), the disability compensation benefit (PCH) and, from 16 years, recognition of disabled worker status (RQTH); in adulthood, social and medico-social support services (SAVS, SAMSAH), university support, employment in ordinary or sheltered settings, adapted housing, renewal of the MDPH file up to 20 years and the allowance for disabled adults; the AFM-Téléthon health pathway referents help to set up these files [1]. The French patient associations indicated are AFM-Téléthon, ECLAS (Ensemble contre l'amyotrophie spinale de type 1) and Familles SMA France, together with the Association des paralysés de France; the French centres are part of ERN EURO-NMD (section 11.3) [1, 5].

10. Illustrative Clinical Case

10.1. Illustrative case (composite, for teaching purposes)

A term male newborn of unrelated Portuguese parents without neuromuscular family history undergoes heel-prick testing on day 4. Screening shows SMN1 exon 7 absence. At day 10, specialist neurological examination shows an alert infant with present tone and tendon reflexes, no tongue fasciculations and normal breathing. MLPA confirms zero SMN1 and two SMN2 copies; ulnar nerve CMAP is 2.1 mV and serum NfL elevated for age. This is presymptomatic 5q SMA at risk of type 1, requiring immediate treatment under the 2018/2020 algorithm [71, 78].

The team discusses the three EU-approved options for this situation. Anti-AAV9 antibodies are negative (titre ≤ 1:50), liver function and platelets normal, and weight 3.6 kg. Intravenous onasemnogene abeparvovec (Zolgensma®) is selected at 1.1 × 10^14 vector genomes/kg on day 18, with oral prednisolone 1 mg/kg/day from the previous day for 30 days, tapered over 28 days; aminotransferases, bilirubin and platelets are monitored weekly during month one, alongside troponin I [21]. In week 3, ALT rises to 3.5 times the upper limit of normal without bilirubin elevation, normalising after two additional weeks of full-dose corticosteroids [21]. Both parents have one SMN1 copy, confirming carrier status and 25% recurrence risk per pregnancy; cascade testing is offered to aunts and uncles and prenatal diagnosis or PGT-M in future pregnancies [6, 8].

He sits unsupported at 9 months, stands with support at 15 and walks independently at 20, resembling two-copy SPR1NT trajectories [111]. Six-monthly multidisciplinary follow-up includes motor assessment (CHOP-INTEND, HINE-2, World Health Organization scales), swallowing, growth, respiratory function, spine and hips, and national registry enrolment [42, 57]. The case illustrates screening, confirmation and treatment within three weeks and the need for long-term surveillance because effect duration and late presymptomatically treated phenotypes remain unknown [8].

10.2. Published case: prenatally diagnosed type 0 SMA and combination treatment

Okubo and colleagues (Sendai, Japan, 2026) described prenatally diagnosed type 0 SMA treated after birth with nusinersen and onasemnogene abeparvovec as early and safely as possible, followed by risdiplam to support motor acquisition [151]. With ongoing physiotherapy, the patient walked independently at 2 years 11 months and developed without swallowing or respiratory difficulty until 3.5 years [151]. The authors emphasise that early combination treatment may benefit severe phenotypes, but absent combination efficacy and safety evidence requires caution and individualisation [151]. Motor progression and treatment chronology figures are available in the original article (https://doi.org/10.1016/j.braindev.2026.104520). Triple treatment is absent from labels and treatment recommendations and is off-label; this individual decision is not routine management (Section 7.8). A second Israeli report (2025) described premature twins born at 32 weeks weighing 1855 g and 1740 g, diagnosed where newborn screening was unavailable but carrier screening widely accepted. They received presymptomatic risdiplam followed by onasemnogene abeparvovec at 35 and 43 weeks of corrected gestational age, adding to limited premature-infant data [152].

10.3. Published case report: SMARD1 in three infants, including twins

Leśniak and colleagues (Szczecin and Wrocław, Poland, 2024) described three female patients with SMARD1 [3]. Patient no. 3, the first daughter of healthy non-consanguineous parents, was born at term weighing 2530 g, with fetal growth restriction from 35 weeks. The neonatal period was uneventful, but from the 2nd month food refusal, poor weight gain, fatigue during feeds, progressive weakness and abnormal foot position appeared. At 3.5 months she presented with grunting, stridor, respiratory effort, axial hypotonia and weak cry; chest radiography showed elevation of the right hemidiaphragm (figure 4 of the article, radiograph at 4 months: https://pmc.ncbi.nlm.nih.gov/articles/PMC11353554/figure/genes-15-00997-f004/). At 4 months she had a respiratory arrest with bradycardia during placement of a gastric tube, reversed by resuscitation. Examination showed tongue fasciculations, generalised hypotonia with reduced reflexes, equinovarus feet and, according to the parents, reduced pain sensitivity; brain and spinal MRI was normal. She underwent tracheostomy at 4.5 months and was discharged on home ventilation. Trio exome sequencing identified NM_002180.3:c.439C>T p.(Arg147Ter), pathogenic, and NM_002180.3:c.1478C>T p.(Thr493Ile), likely pathogenic, in compound heterozygosity confirmed in the parents. At 2.5 years she was fed by gastrostomy, tolerated up to 2 hours off ventilation at rest and had walked with stabilising support since 18 months [3].

The twins (patients no. 1 and no. 2), from a triplet pregnancy of non-consanguineous parents, were born at 33 weeks weighing 1000 g and 880 g with fetal growth restriction, and required non-invasive respiratory support and surfactant in the neonatal period. The first had respiratory failure at 4 months, during a respiratory syncytial virus pneumonia, and underwent tracheostomy at 6 months; the second had her first symptom at 11 months and underwent tracheostomy at 13 months. Initial imaging (radiography in the first, computed tomography in the second) did not show diaphragmatic paralysis, which was only documented by ultrasound at 4 years (bilateral in the first, right-sided in the second). Both developed gastroparesis requiring gastrostomy, constipation, tachycardia, excessive sweating, neurogenic bladder, scoliosis, fatty finger pads and equinovarus feet, and neither sat nor stood independently. Exome sequencing, requested at 14 months for suspected SMA at a time when SMA was not yet part of Polish newborn screening, identified NM_002180.3:c.595G>C p.(Ala199Pro), inherited from the mother and present in the healthy brother, and NM_002180.3:c.1615_1623del p.(Ser539_Tyr541del), inherited from the father; both were initially classified as of uncertain significance and later as likely pathogenic [3]. The report illustrates the variable age at onset between sisters with the same genotype, the absence of eventration at the onset of respiratory distress and the burden of autonomic and digestive dysfunction. The metoprolol used in one of the twins for tachycardia and the other measures described are individual decisions and do not constitute a validated protocol [3].

11. Prognosis and Long-Term Follow-Up

11.1. Prognosis without disease-modifying treatment

Without proactive care, 90% of type 1 patients died before 2 years; type 2 patients survived into adolescence or adulthood, and types 3 and 4 had normal life expectancy with reduced quality of life. Respiratory impairment worsened by scoliosis is the main morbidity determinant [6, 7]. Type 1 natural history placed median age to death or permanent ventilation at 8–13.5 months [39, 40]; Zerres' series estimated type 2 survival at 68.5% by 25 years and type 3 walking retention after 40 years at 22.0% (3a) and 58.7% (3b) [55]. Proactive respiratory and rehabilitation care enables productive lives for many [7].

11.2. Prognosis with treatment

Prognosis now mainly depends on treatment timing, SMN2 copy number and clinical status at initiation. Most presymptomatically treated infants with two or three copies walk independently: 13 of 15 with two copies in NURTURE at 5 years, 14 of 15 with three in SPR1NT, and 42% of RAINBOWFISH at 12 months [100, 106, 119]. Among symptomatic type 1 infants, 29%–59% achieved independent sitting and 85%–97% ventilation-free survival in phase 3 trials, unprecedented in natural history but with residual weakness in most [109, 110, 117]. In later-onset forms and adults, treatment aims at stabilisation or limited functional gains, with ≥ 3 HFMSE points in 28%–40% of adults [105, 107, 118]. New treated phenotypes include residual bulbar weakness, early scoliosis, contractures, hip dislocation and extraneuronal manifestations requiring specific surveillance [8, 38, 59].

11.3. Long-term follow-up

Follow-up should occur at a neuromuscular referral centre with paediatric neurology or neurology, respiratory medicine, gastroenterology and nutrition, rehabilitation medicine, orthopaedics, medical genetics, psychology and social work, at least every 6 months and more often in weaker patients [8, 42, 57]. Surveillance includes validated motor scales (CHOP-INTEND, HINE-2, HFMSE, RULM, 6-minute walk test), respiratory function and polysomnography, swallowing and nutrition, bone mineral density, spine and hip radiographs, and biomarkers (CMAP, NfL) [41, 42, 57]. Onasemnogene abeparvovec recipients require long-term registry follow-up for theoretical vector integration-related tumourigenicity and expression durability [21, 28, 112]. Paediatric-to-adult transition, psychosocial and school support, fatigue and quality of life assessment are included [57]. National and international registries, such as German, Austrian and Swiss SMArtCARE, measure long-term treated outcomes [65]. The relevant European network is ERN EURO-NMD (European Reference Network for rare neuromuscular diseases) [5]; TREAT-NMD maintains global registries and trial resources [150]. Patient organisations include SMA Europe [27], US Cure SMA [153], Portugal's Associação Portuguesa de Neuromusculares (APN) [154] and Brazil's Instituto Nacional da Atrofia Muscular Espinhal (INAME) [155].

11.4. SMARD1: prognosis and surveillance

Without artificial ventilation, mean survival in SMARD1 is about 9 months; in the French series, non-ventilated patients died at a median of 7 months and onset before 3 months was associated with a worse prognosis [4, 63]. With invasive home ventilation, survival of 4.5 to 11 years has been described in the Aachen series and a mean follow-up of 7.8 years in the Berlin series, with loss of function concentrated in the first two years, followed by stabilisation or slight improvement, absence of walking and autonomic dysfunction in all patients [47, 61]. Late-onset forms have a slower course and may allow adult life with ventilation only at night [62]. The prognosis of each ventilated patient depends on respiratory severity, the care provided and complications of ventilation, and there is no validated estimate of life expectancy [4].

The sources consulted do not publish a surveillance protocol specific to SMARD1; the following table brings together the investigations recommended or described in the series and applies, by declared extrapolation, the minimum six-monthly frequency of the 5q SMA standards of care when the SMARD1 source does not define an interval [57].

Sources: [3, 4, 47, 57, 61].

11.5. 5q SMA: surveillance table

The table brings together the intervals of the 2018 international standards and of the French PNDS; where they diverge, the shorter interval is adopted and the source of each is recorded.

Sources: [1, 19, 21, 42, 57, 59].

11.6. Transition to adult care

The PNDS adopts the 2012 French recommendations for young people with motor disability: address transition at the beginning of adolescence or in pre-adolescence (10 to 13 years); transfer during a period of clinical stability, with growth and puberty completed and the paediatric medical-surgical programme at least defined; do not impose an age threshold, 18 years being recommended but not binding against the patient's interest; define in writing, with the adult team, a transition programme in a personalised booklet; carry out a social assessment before the age of majority; progressively make the young person the main interlocutor; promote peer exchange of experiences; rediscuss with the young person the origin and consequences of their disability; identify an adult family doctor; transmit clinical information with the patient's consent; and give visibility to support services and associations [1]. In adults, pain from hip dislocation is treated first with seating adaptation and analgesia, orthopaedic surgery is exceptional and decided in a reference centre, radicular pain is frequent and spinal fusion may limit MRI and injections, lower-limb fracture in type 3 threatens ambulation, and nocturnal hypoventilation, progressive with weakness, requires non-invasive ventilation and, in the most severe forms of type 2, tracheostomy; cough assistance techniques are indispensable, because pulmonary infections cause most hospital admissions [1].

12. Summary and Final Considerations

5q spinal muscular atrophy results from biallelic SMN1 loss of function, usually homozygous exon 7 absence. Severity is mainly modified by SMN2 copy number, a paralogue whose c.840C>T transition excludes exon 7 from most transcripts. The classic types 0–4, based on onset age and maximum motor function, describe a continuum and lose prognostic value in treated patients, particularly those identified by newborn screening. Diagnosis relies on MLPA or quantitative PCR SMN1/SMN2 quantification, supplemented by SMN1 sequencing in single-copy patients. With two or more copies, investigate non-5q SMA including SMARD1 (IGHMBP2), X-linked SMA (UBA1), dominant lower extremity-predominant forms (DYNC1H1, BICD2) and adult-onset VAPB disease with its Portuguese–Brazilian founder variant.

Dosage-based carrier testing has a structural limitation: silent [2+0] carriers and intragenic variants are missed, requiring communication of population- and family-history-adjusted residual risk, potentially refined through duplication-associated variants. Newborn screening, included in Portugal since January 2025 after a pilot with birth prevalence approximately 1:15,000, enables presymptomatic treatment, producing the best outcomes with any approved therapy.

EU and US approvals include intrathecal nusinersen (Spinraza®, high-dose regimen approved in 2026), oral risdiplam (Evrysdi®, solution and 5 mg tablet), intravenous gene therapy (Zolgensma®) and intrathecal gene therapy from age 2 (Itvisma®, FDA November 2025 and EU June 2026); US apitegromab (Isembyld®) was approved in September 2026 as a muscle-directed adjunct. Combination and sequencing evidence comes from open-label studies and case series; fetal therapy remains investigational. Multidisciplinary 2017/2018 standards, updated through later newborn screening, gene therapy, SMN2 genotyping, classification and hip consensuses, remain essential for every patient, treated or untreated.

SMARD1, caused by biallelic IGHMBP2 variants, is the main non-5q SMA with respiratory failure in infancy: diaphragmatic paralysis between 6 weeks and 6 months, a normally shaped chest, predominantly distal weakness, intrauterine growth restriction and autonomic dysfunction. A normal radiograph does not exclude it, newborn screening for SMA does not detect it and diagnosis requires IGHMBP2 sequencing with copy-number analysis and, when necessary, genome and RNA analysis. Treatment is supportive, centred on home ventilation, nutrition, rehabilitation and autonomic surveillance; AAV9-IGHMBP2 gene therapy is in a phase 1/2 trial, without published results.

In France, the HAS PNDS (2021) adds practical rules for respiratory, orthopaedic, digestive, anaesthetic and obstetric care, doses for symptomatic treatments and a structured social pathway; it diverges from the international standards on nutrition and ventilation of infants with severe type 1 in comfort care and on the frequency of surveillance, and it predates the European authorisations of risdiplam, of the intrathecal formulation of onasemnogene abeparvovec and of the high-dose nusinersen regimen [1].

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