Atrofia muscular espinhal não-5q proximal de início no adulto: uma revisão abrangente

Pinto, Wladimir Bocca Vieira de Rezende; Souza, Paulo Victor Sgobbi de; Badia, Bruno Mattos Lombardi; Farias, Igor Braga; Albuquerque Filho, José Marcos Vieira de; Gonçalves, Eduardo Augusto; Machado, Roberta Ismael Lacerda; Oliveira, Acary Souza Bulle

doi:10.1590/0004-282X-ANP-2020-0429

Wladimir Bocca Vieira de Rezende Pinto

Universidade Federal de São Paulo, Departamento de Neurologia e Neurocirurgia, Setor de Investigações nas Doenças Neuromusculares, São Paulo SP, Brazil.

https://orcid.org/0000-0002-0150-525X

Paulo Victor Sgobbi de Souza

Universidade Federal de São Paulo, Departamento de Neurologia e Neurocirurgia, Setor de Investigações nas Doenças Neuromusculares, São Paulo SP, Brazil.

https://orcid.org/0000-0002-7416-7108

Bruno Mattos Lombardi Badia

Universidade Federal de São Paulo, Departamento de Neurologia e Neurocirurgia, Setor de Investigações nas Doenças Neuromusculares, São Paulo SP, Brazil.

https://orcid.org/0000-0001-7360-0494

Igor Braga Farias

Universidade Federal de São Paulo, Departamento de Neurologia e Neurocirurgia, Setor de Investigações nas Doenças Neuromusculares, São Paulo SP, Brazil.

https://orcid.org/0000-0003-2187-6573

José Marcos Vieira de Albuquerque Filho

Universidade Federal de São Paulo, Departamento de Neurologia e Neurocirurgia, Setor de Investigações nas Doenças Neuromusculares, São Paulo SP, Brazil.

https://orcid.org/0000-0002-4533-2637

Eduardo Augusto Gonçalves

Universidade Federal de São Paulo, Departamento de Neurologia e Neurocirurgia, Setor de Investigações nas Doenças Neuromusculares, São Paulo SP, Brazil.

https://orcid.org/0000-0002-9893-2468

Roberta Ismael Lacerda Machado

Universidade Federal de São Paulo, Departamento de Neurologia e Neurocirurgia, Setor de Investigações nas Doenças Neuromusculares, São Paulo SP, Brazil.

https://orcid.org/0000-0002-5842-0062

Acary Souza Bulle Oliveira

Universidade Federal de São Paulo, Departamento de Neurologia e Neurocirurgia, Setor de Investigações nas Doenças Neuromusculares, São Paulo SP, Brazil.

https://orcid.org/0000-0002-6986-4937

Correspondence: Wladimir Bocca Vieira de Rezende Pinto; Email: wladimirbvrpinto@gmail.com.

Conflict of interest: There is no conflict of interest to declare.

Authors’ contributions: WBVRP: conception, organization, and execution of manuscript project, writing of the first draft, and review and critique of manuscript; PVSS, EAG: conception, organization, and execution of manuscript project, writing of the first draft of manuscript; BMLB, JMVAF, RILM: conception, and organization of manuscript project, writing of the first draft of manuscript; IBF, ASBO: conception of manuscript project, writing of the first draft, review and critique of manuscript.

Figuras (2)
Tabelas (4)

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Figure 1
Lower motor neuron anatomical location and structure (A) and non-5q SMA pathophysiological mechanisms (B).

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Figure 2
Diagnostic flowchart for suspected cases of adult-onset proximal spinal muscular atrophy.

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Figure 2
Diagnostic flowchart for suspected cases of adult-onset proximal spinal muscular atrophy.

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Table 1
Classification of primary adult- and childhood-onset motor neuron disease¹1 Souza PVS, Pinto WBVR, Chieia MAT, Oliveira ASB. Clinical and genetic basis of familial amyotrophic lateral sclerosis. Arq Neuro-Psiquiatr. 2015 Dec;73(12):1026-37. https://doi.org/10.1590/0004-282X20150161
https://doi.org/10.1590/0004-282X2015016... ,²2 Garg N, Park SB, Vucic S, Yiannikas C, Spies J, Howells J, et al. Differentiating lower motor neuron syndromes. J Neurol Neurosurg Psychiatry. 2017 Jun;88(6):474-83. https://doi.org/10.1136/jnnp-2016-313526
https://doi.org/10.1136/jnnp-2016-313526... ,³3 Benarroch L, Bonne G, Rivier F, Hamroun D. The 2021 version of the gene table of neuromuscular disorders (nuclear genome). Neuromuscul Disord. 2020 Dec;30(12):1008-48. https://doi.org/10.1016/j.nmd.2020.11.009
https://doi.org/10.1016/j.nmd.2020.11.00... ,⁴4 Pinto WBVR, Debona R, Nunes PP, Assis ACD, Lopes CG, Bortholin T, et al. Atypical Motor Neuron Disease variants: still a diagnostic challenge in Neurology. Rev Neurol (Paris). 2019 Apr;175(4):221-32. https://doi.org/10.1016/j.neurol.2018.04.016
https://doi.org/10.1016/j.neurol.2018.04... ,⁷7 Turner MR, Barnwell J, Al-Chalabi A, Eisen A. Young-onset amyotrophic lateral sclerosis: historical and other observations. Brain. 2012 Sep;135(Pt 9):2883-91. https://doi.org/10.1093/brain/aws144
https://doi.org/10.1093/brain/aws144... .

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Table 2
Current classification of adult-onset spinal muscular atrophy with proximal predominance, according to the involved pattern of inheritance³3 Benarroch L, Bonne G, Rivier F, Hamroun D. The 2021 version of the gene table of neuromuscular disorders (nuclear genome). Neuromuscul Disord. 2020 Dec;30(12):1008-48. https://doi.org/10.1016/j.nmd.2020.11.009
https://doi.org/10.1016/j.nmd.2020.11.00... ,⁴4 Pinto WBVR, Debona R, Nunes PP, Assis ACD, Lopes CG, Bortholin T, et al. Atypical Motor Neuron Disease variants: still a diagnostic challenge in Neurology. Rev Neurol (Paris). 2019 Apr;175(4):221-32. https://doi.org/10.1016/j.neurol.2018.04.016
https://doi.org/10.1016/j.neurol.2018.04... ,⁶6 Kolb SJ, Kissel JT. Spinal muscular atrophy. Neurol Clin. 2015 Nov;33(4):831-46. https://doi.org/10.1016/j.ncl.2015.07.004
https://doi.org/10.1016/j.ncl.2015.07.00... ,⁸8 Farrar MA, Kiernan MC. The genetics of Spinal Muscular Atrophy: progress and challenges. Neurotherapeutics. 2015 Apr;12(2):290-302. https://doi.org/10.1007/s13311-014-0314-x
https://doi.org/10.1007/s13311-014-0314-... ,⁹9 Zerres K, Rudnik-Schöneborn S. 93rd ENMC international workshop: non-5q spinal muscular atrophies (SMA) – clinical picture (6-8 April 2001, Naarden, The Netherlands). Neuromuscul Disord. 2003 Feb;13(2):179-83. https://doi.org/10.1016/s0960-8966(02)00211-0
https://doi.org/10.1016/s0960-8966(02)00... ,¹⁰10 Wee CD, Kong L, Sumner CJ. The genetics of spinal muscular atrophies. Curr Opin Neurol. 2010 Oct;23(5):450-8. https://doi.org/10.1097/WCO.0b013e32833e1765
https://doi.org/10.1097/WCO.0b013e32833e... ,¹¹11 Peeters K, Chamova T, Jordanova A. Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies. Brain. 2014 Nov;137(11):2879-96. https://doi.org/10.1093/brain/awu169
https://doi.org/10.1093/brain/awu169... ,¹²12 Souza PVS, Bortholin T, Naylor FGM, Chieia MAT, Pinto WBVR, Oliveira ASB. Motor neuron disease in inherited neurometabolic disorders. Rev Neurol (Paris). 2018 Mar;174(3):115-24. https://doi.org/10.1016/j.neurol.2017.06.020
https://doi.org/10.1016/j.neurol.2017.06... ,¹⁴14 Darras BT. Non-5q spinal muscular atrophies: the alphanumeric soup thickens. Neurology. 2011 Jul;77(4):312-4. https://doi.org/10.1212/WNL.0b013e3182267bd8
https://doi.org/10.1212/WNL.0b013e318226... .

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Table 3
Red-flag signs to consider a possible non-5q (non-SMN1/SMN2) form of spinal muscular atrophy¹¹11 Peeters K, Chamova T, Jordanova A. Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies. Brain. 2014 Nov;137(11):2879-96. https://doi.org/10.1093/brain/awu169
https://doi.org/10.1093/brain/awu169... ,¹²12 Souza PVS, Bortholin T, Naylor FGM, Chieia MAT, Pinto WBVR, Oliveira ASB. Motor neuron disease in inherited neurometabolic disorders. Rev Neurol (Paris). 2018 Mar;174(3):115-24. https://doi.org/10.1016/j.neurol.2017.06.020
https://doi.org/10.1016/j.neurol.2017.06... ,¹⁴14 Darras BT. Non-5q spinal muscular atrophies: the alphanumeric soup thickens. Neurology. 2011 Jul;77(4):312-4. https://doi.org/10.1212/WNL.0b013e3182267bd8
https://doi.org/10.1212/WNL.0b013e318226... .

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Table 4
Clues in the differential diagnosis of suspected genetic basis of proximal spinal muscular atrophy³3 Benarroch L, Bonne G, Rivier F, Hamroun D. The 2021 version of the gene table of neuromuscular disorders (nuclear genome). Neuromuscul Disord. 2020 Dec;30(12):1008-48. https://doi.org/10.1016/j.nmd.2020.11.009
https://doi.org/10.1016/j.nmd.2020.11.00... ,⁹9 Zerres K, Rudnik-Schöneborn S. 93rd ENMC international workshop: non-5q spinal muscular atrophies (SMA) – clinical picture (6-8 April 2001, Naarden, The Netherlands). Neuromuscul Disord. 2003 Feb;13(2):179-83. https://doi.org/10.1016/s0960-8966(02)00211-0
https://doi.org/10.1016/s0960-8966(02)00... ,¹⁰10 Wee CD, Kong L, Sumner CJ. The genetics of spinal muscular atrophies. Curr Opin Neurol. 2010 Oct;23(5):450-8. https://doi.org/10.1097/WCO.0b013e32833e1765
https://doi.org/10.1097/WCO.0b013e32833e... ,¹¹11 Peeters K, Chamova T, Jordanova A. Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies. Brain. 2014 Nov;137(11):2879-96. https://doi.org/10.1093/brain/awu169
https://doi.org/10.1093/brain/awu169... ,¹²12 Souza PVS, Bortholin T, Naylor FGM, Chieia MAT, Pinto WBVR, Oliveira ASB. Motor neuron disease in inherited neurometabolic disorders. Rev Neurol (Paris). 2018 Mar;174(3):115-24. https://doi.org/10.1016/j.neurol.2017.06.020
https://doi.org/10.1016/j.neurol.2017.06... ,¹⁴14 Darras BT. Non-5q spinal muscular atrophies: the alphanumeric soup thickens. Neurology. 2011 Jul;77(4):312-4. https://doi.org/10.1212/WNL.0b013e3182267bd8
https://doi.org/10.1212/WNL.0b013e318226... .

Classification of Motor Neuron Disease (MND) group^* * Primary MND group includes distinct clinical conditions which result from primary compromise and neurodegeneration of the lower and/or upper motor neurons;
Upper and lower MND
	Amyotrophic Lateral Sclerosis (ALS) (sporadic, familial; juvenile) Mills’ syndrome (progressive hemiplegic variant)^ the classification of Mills’ syndrome as an ALS or PLS variant is still a matter of debate;
Upper MND
	Primary Lateral Sclerosis (PLS) (sporadic, familial)
Lower MND
	Progressive Muscular Atrophy (Duchenne-Aran syndrome) (sporadic)
	SMN1-associated (5q) Spinal Muscular Atrophy (SMA) (hereditary)
	Non-5q (non- SMN1/SMN2) SMA (familial, hereditary)
	Distal SMA (distal hereditary motor neuronopathy)
	Proximal non-5q SMA
	“Flail-arm” syndrome (Vulpian-Bernhardt) (sporadic, familial)
	O’Sullivan-McLeod syndrome (sporadic)
	Hirayama disease (Juvenile monomelic distal amyotrophy) (sporadic)
	“Flail-leg” syndrome (pseudopolyneuritic form) (sporadic)
MND with marked bulbar and cranial nerve involvement
	Progressive Bulbar Palsy (sporadic)
	Kennedy’s disease (X-linked spinal and bulbar muscular atrophy) (familial, hereditary)
	Fazio-Londe disease (Juvenile Progressive Bulbar Palsy) (sporadic, familial)
	Brown-Vialetto-van Laere syndrome (sporadic, familial)
	Madras MND (sporadic, familial)
	FOSMN syndrome^* ***** FOSMN is currently included in the group of primary MND, despite its rare occurrence, due to the major neuropathological, laboratory, and neuroimaging evidence linking to ALS-like phenotype and biomarkers. (sporadic, familial)

Adult-onset SMA with proximal predominance^* * distal SMA [spinal muscular atrophy] (or distal hereditary motor neuronopathy) presentations are not included;
I. Autosomal dominant pattern of inheritance
	Finkel type SMA (related to VAPB gene variants) Jokela type SMA (related to CHCHD10 gene variants) Adult-onset scapuloperoneal syndrome linked to TRPV4 gene variants Okinawa type SMA (proximal hereditary sensory and motor neuronopathy) Adult-onset proximal SMA with cardiac involvement (LMNA variants) SMA with retained/brisk reflexes (motor neuronopathy with pyramidal release signs (SETX variants) SMA with lower extremity dominant (SMALED) type 2A – atypical late-onset (BICD2 variants)^ limited data restricted to case reports or small case series. Lower motor neuron disease with respiratory failure associated with MAPT gene variants
II. Autosomal recessive pattern of inheritance
	SMA type IV (adult form of 5q SMA) GM2 gangliosidosis: Adult-onset Tay-Sachs disease (atypical), Sandhoff disease (late adult-onset associated with HEXB variants); AB variant (GM2A activator deficiency) Late adult-onset primary defects of riboflavin transporter (Fazio-Londe disease and Brown-Vialetto-van Laere syndrome) Late-onset Spinal Muscular Atrophy associated with Progressive Myoclonic Epilepsy (SMA-PME) due to acid ceramidase deficiency (ASAH1 variants) Late-onset SMA with Respiratory Distress (SMARD) due to IGHMBP2 variants SMA with lower extremity dominant type 1 – atypical late-onset (DYNC1H1 variants)^ limited data restricted to case reports or small case series.
III. X-linked pattern of inheritance
	X-linked Spinal and Bulbar Muscular Atrophy (Kennedy’s disease)

Red-flag signs for a non-5q SMA presentation
Disproportionate distal to proximal motor compromise, even in the context of a marked proximal involvement (context of distal hereditary motor neuronopathy — distal SMA)
Specific findings and neurological contexts: arthrogryposis multiplex congenita, vocal cord palsy, diaphragmatic palsy with severe early-onset acute respiratory failure, multiple cranial nerve palsy, progressive myoclonic epilepsy, sensorineural hearing loss, mild pyramidal release signs (similar phenotypes to ALS)
Abnormal findings in neuroimaging studies: pontocerebellar hypoplasia, hypomyelination, leukodystrophy, malformations of central nervous system due to abnormal development
Specific neuroophthalmological findings (e.g. cataracts, optic atrophy, retinitis pigmentosa)
Other specific systemic findings (e.g. cardiomyopathy, endocrinopathy)
Familial spectrum of neurological or systemic compromise associated with other red-flag signs for a possible non-5q SMA

Clinical, neuroimaging and laboratorial clues in the evaluation of suspected proximal SMA
I. Age at onset	Very early (neonatal or infancy-onset; <2 years): SMN1, SLC52A2, SLC52A3, GLE1, VRK1, GLE1, UBA1, EXOSC8, EXOSC3, TK2, TRPV4* Early (early and late childhood-onset): SMN1, DYNC1H1, BICD2, TRPV4, SLC52A2, SLC52A3, ASAH1, LAS1L, TRPV4 Late (juvenile and adult-onset): SMN1, VAPB, TFG, AR, LMNA, SETX, CHCHD10, HEXA, HEXB, GM2A, TRPV4, ASAH1, SLC52A2, SLC52A3, BICD2, DYNC1H1
II. Pattern of inheritance	AR: SMN1, SLC52A2, SLC52A3, HEXA, HEXB, GM2A, ASAH1, VRK1, EXOSC3, EXOSC8, GLE1, IGHMBP2 AD: VAPB, TRPV4, TFG, CHCHD10, SETX, LMNA, DYNC1H1, BICD2, GLE1 XLR: AR, UBA1, LAS1L
III. LGMW phenotype	Lower extremity predominance: DYNC1H1, BICD2, SMN1, VAPB Scapuloperoneal pattern: TRPV4, SLC52A3* Moderate/severe axial involvement: SMN1, VRK1, AR, SLC52A2, SLC52A3
IV. Bulbar-dominant phenotype	Dysphagia/dysphonia: SMN1, AR, SLC52A2, SLC52A3, VRK1, TFG (late stages), HEXB*
V. Multiple cranial neuropathies	Sensorineural hearing loss: SLC52A2, SLC52A3, TRPV4 Vocal cord paralysis: TRPV4
VI. Neuro-ophthalmological disturbances	Optic atrophy: SLC52A2, SLC52A3, Pigmentary retinopathy: SLC52A2, SLC52A3,
VII. Other neurological or neuromuscular compromise	Cerebellar ataxia: SLC52A2, SLC52A3, HEXA, HEXB, GM2A, VRK1 Postural tremor/polyminimyoclonus: VAPB, AR, TFG, SMN1, HEXB Parkinsonism/Dystonia: HEXA, HEXB, GM2A Myoclonus/PME: ASAH1, HEXA Cognitive decline: HEXA, HEXB, SLC52A2, SLC52A3 Intellectual disability: VRK1, EXOSC3, EXOSC8, ASAH1 Dysautonomia: VAPB, AR; IGHMBP2 Pyramidal signs: SETX, SLC52A2, SLC52A3, VAPB*
VIII. Neuroimaging findings	Pontocerebellar hypoplasia: VRK1, EXOSC3, EXOSC8 Cerebellar atrophy: SLC52A2, SLC52A3, HEXA, HEXB, GM2A, TK2* Hypomyelination: EXOSC8
IX. Associated neurophysiological findings	Reduced SNAP amplitude: AR, TFG, SLC52A2, SLC52A3 Pseudo-myotonic discharges: SMN1, TFG
X. Respiratory compromise	Diaphragmatic involvement: IGHMBP2, LAS1L, ASAH1, SMN1, TK2* Restrictive lung disease: UBA1, SMN1, GLE1, TK2*
XI. Miscellaneous	Multiple contracture/arthrogryposis multiplex: GLE1, UBA1, BICD2, DYNC1H1, TRPV4, SMN1* Pes cavus, pes planus: DYNC1H1, BICD2, AR, SLC52A2, SLC52A3, TFG* Diabetes and other endocrine diseases: AR, TFG Cardiomyopathy: LMNA, AR High serum CK levels: TFG, AR, VAPB, SMN1, TRPV4, TK2 Worse prognosis (early death): SMN1, VRK1, EXOSC3, EXOSC8, GLE1, UBA1, TK2* Ancestry (family origin): Japan, Taiwan, South Korea (TFG, AR); Brazilian (VAPB); Finland (CHCHD10)

[1] Correspondence: Wladimir Bocca Vieira de Rezende Pinto; Email: wladimirbvrpinto@gmail.com.

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Atrofia muscular espinhal não-5q proximal de início no adulto: uma revisão abrangente

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