(proximal spinal muscular atrophy, SMA (Spinal Muscular Atrophy), Aran-Duchenne disease,Werdnig-Hoffman disease, Kugelberg-Welander-Wohlfart disease )

Rare: 1/6,000 live births in Europe. Autosomal recessive transmission of a mutation of the SMN1 gene (5q13.2),  responsible for the synthesis of SMN1, a protein essential to the survival of motor neurons. The mutation causes neurological disease with muscle atrophy due to the degeneration of spinal motoneurons. 

Classically, five clinical forms are described but the evolution of the patients is modified by the recently introduced therapies:

-   SMA type I or infantile or Werdnig-Hoffmann disease [MIM 253 300] (see this term): most severe form; onset in the first 6 months of life: the child never acquires the sitting position; hypotonia with symmetric and rapidly progressive paralysis of the four limbs, lingual twitching, major respiratory failure caused by intercostal muscles paralysis, early death (< 2 years); a hypoplastic left heart, or ASD or VSD can be associated

-         SMA type II or juvenile [MIM 253 550]: onset between 6 and 12 months of age; type 2a: the child can sit but cannot stand; type 2b: the child can stand and take a few steps with help. Early dorsolombar kyphosis (< 3 years of age) and hypotonic scoliosis (90 %); contractures of some joints and dislocation of the hip; tremulation of the tongue and extremities. Frequent osteoporosis due to immobilization. Restrictive syndrome and alveolar hypoventilation with a narrow chest as a consequence of the involvement of the intercostal, abdominal and spinal muscles. Frequent gastroparesis and significant risk of acute gastric dilation (25 %). Midface hypoplasia following the chronic application of a NIV mask. Risk of undernutrition or obesity. Survival until adulthood; swallowing disorders

-         SMA type III or Kugelberg-Welander-Wohlfart disease [MIM 253 400] (see this term) (< 15 % of cases): onset after 2 year of age; the child is able to walk with difficulty; scoliosis; survival to adulthood; some cases of cardiomyopathy have been described

-         SMA type IV [MIM 271 150]:  (< 5 % of cases): onset after 18 year of age;adult form characterized by a progressive paralysis of the lower limbs with loss of the patellar reflexes: the patients remain mobile until 50 year of age; respiratory, bulbar and visceral involvement is rare; sometimes respiratory problems; life expectancy is unaffected.

-         SMA type 0: neonatal form with major hypotonia and respiratory distress at birth, involvement of the facial nerves (sucking and swallowing are impossible); prenatal signs: decreased fetal movements, multiple arthrogryposis congenita, cardiac anomalies; rapid death within the first months of life

Possible treatments:

-         replacement of the SMN1 protein (viral vector): onasemnogene abeparvovec IV. Monitoring: platelets and liver enzymes: SMA 1 and 2

-         increased production of the SMN2 protein: nusinersen (Spinraza®) intrathecally every 4 months, or risdiplam orally daily: SMA 1, 2 and 3

-         as many patients show signs of neuromuscular junction fatigability, adjuvant treatment with salbutamol may be combined with this treatment

There are other less frequent forms:

a) Spinal proximal Muscular Atrophies not related to the SMN1 gene  

• SMA-AR: recessive transmission, onset after 10 years of age, HEXA gene (15q23-q24) or HEXB (5q13); in the context of GM2 gangliosidosis (Tay-Sachs diseases, Sandhoff) with an evolution similar to SMA type III
• autosomal recessive distal amyotrophy or SMA-PCH1 [MIM 602 168]: recessive, onset in utero or before 6 months of age; VRK1 gene in 14q32.2; phenotype similar to SMA type 1 or 2
• recessive spinal muscular atrophy with pontocerebellar hypoplasia [MIM 616 801]: EXOSC8 gene (13q13.3)
• ADM-AD: autosomal dominant, juvenile form that begins between 5 and 20 years of age
• SMA-AD: autosomal dominant, adult form that begins after 25 years of age, very slow evolution; LMNA gene (1q22) coding for lamine or, for the Finkel type (SMAFK), VAPB (20q13.3) [MIM 182 980]
• Jokela spinal muscular atrophy [MIM 615 048]: autosomal dominant transmission of a mutation of the CHCHD10 gene (22q11.23)
• X-linked recessive spinal muscular atrophy with arthrogryposis (UBA1 gene (Xp11.3)) (SMAX2) [MIM 301 830]: phenotype of congenital or infantile spinal muscular atrophy with arthrogryposis sometimes called Kennedy disease type 2
• ADM-SME [MIM 159 950]: autosomal recessive, associated with progressive myoclonic epilepsy; ASAH1 gene (8p22)

b) Spinal Muscular Atrophies:  distal and/or generalised affecting primarily the distal limbs

• hereditary distal motor neuropathy type I or d-HMN I [MIM 182 960]: autosomal dominant, onset between 1 and 20 years of age, distal muscle weakness, mutation of the HMN1 gene (7q34-q36)
• hereditary distal motor neuropathy type II or d-HMN II: autosomal dominant, onset between 20 and 40 years of age, distal weakness; HSPB8 (12q24.2) (type IIA) [MIM 158 590], HSPB1 (7q11.23) [MIM 608 634] (type IIB), HSPB3 (5q11.2) (type IIC) [MIM 613 634] or FBX038 (type IID) [MIM 615 575]
• hereditary distal motor and sensory neuropathy type V [MIM 600361]: autosomal dominant transmission of a mutation in 4q34.3-q35.2
• hereditary distal motor neuropathy type IX [MIM 617 772]: autosomal dominant transmission of a mutation of the WARS gene  (14q32.2)
• d-HMN III/IV [MIM 611 067] or DSMA4: autosomal recessive, onset between 2 months and 20 years of age; distal and proximal weakness; PLEKHG5 gene (1p36. 1)
• dHMNJ or autosomal recessive distal spinal muscular atrophy type 2 or DSMA2 or hereditary spinal muscular atrophy type Jerash [MIM 605 726]: autosomal recessive, SIGMAR1 gene (9p13.3); beginning between 6 and 10 years of age, distal involvement beginning with the lower limbs (varus feet, hammer toes, claw fingers) with pyramidal signs that disappear gradually.
• distal spinal muscular atrophy or d-HMN V: autosomal dominant, early between 5 and 20 years of age; it mainly affects the upper limbs; GARS (7p15) (type V), REEP1 (type VA) [MIM 614 751] or BSCL2 (11q12-q14) (type VB) genes [MIM 619 112]
• d-HMN VI or DSMA1 or SMARD1 (infantile spinal muscular atrophy with respiratory distress type 1) (MIM 604 320) or hereditary motor neuropathy type 6: autosomal recessive, onset before 1 year; spinal amyotrophy phenotype that mainly affects distal muscles with diaphragmatic paralysis and respiratory distress; IGHMBP2 gene (11q13.3)
• hereditary distal motor neuropathy type VII or d-HMN VII or Harper-Young myopathy: autosomal dominant, early between 10 and 20 years of age; affects mainly the upper limbs, paresis of the vocal cords; SLC5A7 gene (2q12.3) (type VII A) [MIM 158 580] or DCTN1 (2p13.1) (type VII B)[MIM 607 641]
• autosomal dominant spinal muscular atrophy of childhood with predominance to the lower limbs (or SMA-LED, acronym for Spinal Muscular Atrophy with Lower Extremity preDominance): dyneinopathy due to de novo or autosomal dominant transmission of a mutation

• of the DYNC1H1 gene (14q32.31) [MIM 158 600]: type 1. Abnormality of cytoplasmic dynein, aprotein involved in axonal transport in motor neurons. Pseudomyopathic presentation: weakness of the lower limbs, amyotrophy, difficult walking, deformation of the feet, joint contractures. Other mutations of the same gene can lead to Charcot-Marie-Tooth 2O disease or mental retardation
• of the BICD2 gene (9q22.31):

* type 2A [MIM 615 290]: weakness of the lower limbs, amyotrophy, difficult walking, deformation of the feet, joint contractures

* type 2B [MIM 615 291]: very early onset, more severe evolution

• X-linked chronic d-SMA (SMAX3):onset between 1 month and 20 years of age; distal weakness (ATP7A gene (X12q21.1)) [MIM 300,489], sometimes called Kennedy's disease type 3
• non-progressive distal congenital spinal muscular atrophy: autosomal dominant, onset before 1 month of age: distal involvement with contractures; TRPV4 gene in 12q24.11 if HMN8 [MIM 600 175]; there is a scapuloperoneal form SPSMA [MIM 181 405]; other mutations of this gene can give Charcot-Marie-Tooth disease type 2C.
• SYT2-related distal motor neuropathy: autosomal dominant transmission of a mutation of the SYT2 gene (1q32.1)
• distal motor neuropathy: autosomal dominant transmission of a mutation of the SPTAN1 gene (9q34.11)
• LCCS1: autosomal recessive transmission of a mutation of the  GLE1  gene (9q34), onset in utero;  lethal congenital contracture syndrome type I [fetal hydrops, akinesia];
• LCCS2: autosomal recessive transmission of a mutation of the ERBB3 gene (12q13), onset in utero; lethal congenital contracture syndrome type II [polyhydramnios, akinesia, neurogenic bladder];
• LCCS3: autosomal recessive transmission of a mutation of the PIP5K1C gene (19p13.3), onset in utero; lethal congenital contracture syndrome  type III [polyhydramnios, akinesia]; 

c) bulbar or bulbospinal Spinal Muscular Atrophies: degeneration of motoneurons of the lower part of the brain stem

-        Fazio-Londe disease: autosomal dominant or recessive inheritance, onset between 1 and 20 years of age; progressive bulbar palsy

-        Brown-Vialetto-Van Laere disease: autosomal recessive inheritance of a mutation of the SLC52A3 gene (20p13) (type 1) [MIM 211 530] or of the SLC52A2 gene (8q24.3) (type 2) [MIM 614 707]; onset between 2 months and 20 years of age. Progressive bulbar palsy with deafness

-        Kennedy disease (MIM 313 200): X-linked transmission of a mutation of the AR gene (Xq11-q12); onset after 20 years of age; the bulb is affected: progressive proximal weakness; insensitivity to androgens; dysarthria, dysphagia.

Anesthetic implications: 

at least for the clinical forms linked to SMN1 gene: denervation causes a change in the composition of the muscle fibres i.e. a decrease in glycogen, an alteration of the β-oxidation of fatty acids and a secondary deficiency in carnitine. The more severe the phenotype, the more these changes are. These patients are therefore in a metabolic situation similar to those suffering of a  anomaly of the ß-oxidation of fatty acids with a risk of acute hepatic failure (Reye-like syndrome) in case of catabolism. It is therefore important to administer enough glucose to avoid lipid catabolism, provide carnitine supplements and avoid using a continuous infusion of propofol .

Risk of difficult intubation: progressive ankylosis of the temporomandibular joint and decrease in cervical mobility (muscular contracture or secondary to the scoliosis repair). Mask ventilation is usually not difficult. Use of videolaryngoscopy is recommended.

The use of locoregional anesthesia is a subject of controversy: the risk of aggravating the evolution at the spinal level (motor neurons) or peripheral (axopathy)  level is unknown and must be assessed according to each patient.

The intrathecal injections can be performed under local anesthesia with or without sedation, or under general anesthesia (facial or laryngeal mask) according to the age, clinical status and preferences of the child. In case of scoliosis (with or without arthrodesis), some teams use a CT-scan or ultrasound-guided approach (paramedian or paraspinal approach).

Restrictive respiratory failure in types I and II (often non-invasive ventilation during night or daytime). Swallowing disorders. Risk of hypoglycemia due to muscle wasting and malnutrition. Osteoporosis, scoliosis. 

NO succinylcholine: potential risk of hyperkalemia. Difficult monitoring of neuromuscular function.

SMA I :         often hypoplastic left heart syndrome, or ASD or associated VSD; early feeding by gastrostomy. Midface hypoplasia due to non-invasive ventilation by facemask. Risk of sudden death. Locoregional anesthesia has been used with success. Intrathecal administration of nusinersen allows to recover some motricity and improves the quality of live. Risk of hepatotoxicity in case of gene therapy by onasemnogene.

SMA II :         non-invasive  ventilation;  growth retardation (rarely obesity by inactivity), osteoporosis, early severe scoliosis. Risk of difficult intubation: midface hypoplasia, paralysis of the facial muscles, contracture of the masseters. Regional anesthesia has been used successfully.

SMA III : regional anesthesia used successfully.

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Updated: October 2023