Consenso da Academia Brasileira de Neurologia para diagnóstico, aconselhamento genético e uso de terapias modificadoras na atrofia muscular espinhal 5q

Zanoteli, Edmar; Araujo, Alexandra Prufer de Queiróz Campos; Becker, Michele Michelin; Fortes, Clarisse Pereira Dias Drumond; França Jr., Marcondes Cavalcante; Machado-Costa, Marcela Camara; Marques Jr., Wilson; Matsui Jr, Ciro; Mendonça, Rodrigo Holanda; Nardes, Flávia; Oliveira, Acary Souza Bulle; Pessoa, Andre Luis Santos; Saute, Jonas Alex Morales; Sgobbi, Paulo; Van der Linden Jr., Hélio; Gurgel-Giannetti, Juliana

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Brazilian Academy of Neurology • Arq. Neuro-Psiquiatr. 82 (1) • 2024 • https://doi.org/10.1055/s-0044-1779503 copiar

Consenso da Academia Brasileira de Neurologia para diagnóstico, aconselhamento genético e uso de terapias modificadoras na atrofia muscular espinhal 5q

Autoria SCIMAGO INSTITUTIONS RANKINGS

Resumo

Atrofia muscular espinhal ligada ao cromossomo 5 (AME-5q) é uma doença genética de herança autossômica recessiva causada por mutações no gene SMN1. A AME-5q cursa com degeneração progressiva dos motoneurônios medulares e bulbares, acarretando grave comprometimento motor e respiratório com redução da sobrevida, especialmente nas suas formas clínicas mais graves. Nos últimos anos, terapias modificadoras da doença altamente eficazes, ou que atuam regulando o splicing do exon 7 do gene SMN2 ou adicionando uma cópia do gene SMN1 via terapia gênica, têm surgido, proporcionando uma mudança drástica na história natural da doença. Dessa forma, o desenvolvimento de guias terapêuticos e de consensos de especialistas torna-se importante no sentido de direcionar o uso dessas terapias na prática clínica. Este consenso, preparado por especialistas brasileiros, teve como objetivos revisar as principais terapias modificadoras de doença disponíveis, analisar criticamente os resultados dos estudos clínicos dessas terapias e prover recomendações para seu uso na prática clínica para pacientes com AME-5q. Aspectos relativos ao diagnóstico, aconselhamento genético e seguimento dos pacientes em uso das terapias também são abordados nesse consenso. Assim, esse consenso promove valiosas informações a respeito do manejo atual da AME-5q auxiliando decisões terapêuticas na prática clínica e promovendo ganhos adicionais nos desfechos finais.

Palavras-chave
Atrofia Muscular Espinhal; Proteína 1 de Sobrevivência do Neurônio Motor; Oligonucleotídeos; Risdiplam; Terapia Genética; Onasemnogene abeparvovec

SMA type	Prevalence	Symptoms onset	Maximum motor ability	Subclassification	SMN2 copy number
Type 0	Unknown	Pre-natal	None	–	1 copy
Type 1	60%	0-6 months	Hold the head	1A: start < 1 month. 1B: Start in 1-3 months. 1C: Start in 3-6 months.	1-2 copies
Type 2	27%	7-18 months	Sit	2A: Sit without support but lose this capacity. 2B: Sit without support but maintain this capacity.	3 copies in more than 70% of patients
Type 3	12%	> 18 months	Walk	3A: Start in 18-36 months. 3B: Start after 36 months.	3-4 copies in more than 95% of patients
Type 4	1%	> 18 years	Walk		4 or more copies in more than 90% of patients

CHOP INTEND	HFMSE	RULM	6MWT
All children <2 years old All patients > 2 years old without the ability to sit	All patients >2 years old with the ability to sit If CHOP INTEND score > 50: CHOP INTEND and HFSME If CHOP INTEND score > 60: HFMSE instead of CHOP INTEND	All patients > 2 years old with the ability to sit (in a wheelchair)	All ambulant patients > 3 years old

	Assessment of non-sitters	Assessment of sitters	Assessment of walkers
Motor function	HINE-2, CHOP INTEND (or CHOP ATEND for adults), RULM	HINE-2, CHOP INTEND (or CHOP ATEND for adults), HFSME, RULM, MFM32	HFSME, 6MWT, MFM32, RULM, Timed-test (time needed to walk 10 m, arise from the floor, and climb steps)
Respiratory function	Need of NIV or IV, changes in time required for NIV, number of recurrent pulmonary infections, hospitalizations (number of days a year)	Need of NIV or IV, changes in time required for NIV, number of recurrent pulmonary infections, hospitalizations (number of days a year) PCF Spirometry (≥ 6 years old): FVC, PEF	Spirometry (≥ 6 years old): FVC, PEF PCF
Bulbar function	Need of nasogastric tube or gastrostomy; Videofluoroscopic swallow study or clinical assessment of the risk of aspiration	Need of nasogastric tube or gastrostomy Videofluoroscopic swallow study or clinical assessment of the risk of aspiration
Nutritional status	Clinical evaluation: Weight, height BMI Percentile > 3 Z-score > −2	Clinical evaluation: Weight, height BMI Percentile > 3 Z-score > −2	Clinical evaluation: Weight, height BMI Percentile > 3 Z-score > −2

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[1] Address for correspondence Edmar Zanoteli (email: edmar.zanoteli@usp.br)

Confirmation of biallelic pathogenic variant in SMN1 gene	To establish a genetic diagnosis of SMA-5q, it is essential to demonstrate the presence of a biallelic pathogenic variant in the SMN1 gene
MLPA technique for detection of deletion in exons 7 and 8 of SMN1	The MLPA technique is a reliable method for detecting deletions in specific exons of the SMN1 gene, particularly exons 7 and 8. Additionally, MLPA can also be used to determine the number of copies of the SMN2 gene, which is a related gene that influences the severity of SMA
Sequencing of SMN1 gene for atypical cases	In cases where individuals show clinical symptoms of SMA but only demonstrate deletion in one copy of the SMN1 gene (heterozygous deletion), or no deletion at all (especially in cases of consanguineous parents), further testing is necessary. For such cases, sequencing of the entire coding region of the SMN1 gene and splicing regions located at the intron-exon junction should be performed. This search aims to identify small-scale pathogenic variants in one or both alleles that might not be detected by the MLPA technique
Genetic testing for babies born to mothers with SMA history	Newborn babies born to mothers with a previous history of other children diagnosed with SMA should undergo genetic testing at birth. Early genetic testing allows for early detection and intervention if SMA is confirmed
Investigation of other neuromuscular causes	In cases where individuals present clinical symptoms of SMA-5q, but no deletion is detected in the SMN1 gene and/or the sequencing of the entire coding region of the SMN1 gene appears normal, it is important to investigate other potential neuromuscular causes
Newborn screening for SMA	Neonatal screening for SMA is an effective strategy to identify affected individuals in pre-symptomatic stage or during the early stage of clinical impairment

Efficacy and safety in pre-symptomatic and SMA types 1, 2, and 3	Nusinersen has been shown to be effective and safe for the treatment of patients in the pre-symptomatic stage and those with SMA types 1, 2, and 3
Limited data for SMA types 0 and 4	The effectiveness and safety of nusinersen for patients with SMA types 0 and 4 are not yet well-established due to limited data
Less favorable outcome in severe motor and respiratory impairment	Patients with severe motor and respiratory impairment may have minor expectations for benefits with nusinersen treatment. The response to treatment may be influenced by the severity of the disease, irreversible loss of motor neurons, and associated complications
Contraindications for nusinersen	Nusinersen is contraindicated in patients at risk of repeated intrathecal administration, which includes conditions such as intracranial hypertension, hydrocephalus, and spinal dysraphism
Special considerations for severe scoliosis or previous spine surgery	In patients with severe scoliosis or a history of spine surgery, the administration of nusinersen should be performed by an experienced healthcare professional. Additionally, the use of auxiliary imaging methods like ultrasound, tomography, or fluoroscopy may be necessary to ensure safe and accurate delivery of the drug
Regular monitoring for adverse events	Patients receiving nusinersen treatment should be regularly monitored for potential adverse events. Monitoring every 6 months for urine protein, platelets, and renal function is recommended. Depending on the occurrence of adverse events, some patients may require more frequent testing

Efficacy and safety in pre-symptomatic and SMA types 1, 2, and 3	Risdiplam has been shown to be effective and safe for the treatment of patients in pre-symptomatic stage and those with SMA types 1, 2, and 3
Limited data for SMA types 0 and 4	The effectiveness and safety of risdiplam for patients with SMA types 0 and 4 are not well-established due to limited data
Long-term safety and age considerations	Additional studies are required to evaluate the long-term safety and efficacy of risdiplam, especially for individuals over 25 years of age. The safety evidence for risdiplam, based on scientific publications, currently spans up to 4 years
Less favorable outcome in severe motor and respiratory impairment	Patients with severe motor and respiratory impairment may have minor expectations for the benefits of risdiplam treatment. The response to treatment may be influenced by the severity of the disease, irreversible loss of motor neurons, and associated complications
Laboratory follow-up	Although general laboratory abnormalities are not frequently reported in patients taking risdiplam, follow-up monitoring every 6 months for urine protein, renal function, and serum platelets and liver enzymes is recommended

Efficacy for pre-symptomatic and SMA type 1	Gene replacement therapy has shown to be effective for patients in pre-symptomatic stage and those with SMA type 1, up to 6 months old
Efficacy for SMA types 1 and 2, up to 24 months	Gene therapy is considered effective for patients with SMA types 1 and 2, aged up to 24 months, with a body weight of up to 13.5 kg
Favorable risk/benefit ratio	The risk/benefit ratio of gene therapy treatment is favorable for individuals in pre-symptomatic stage of SMA and for patients with SMA types 1 and 2 up to 24 months of age, with a body weight of up to 13.5 kg. However, it is important to note that the occurrence of complications related to gene therapy may increase with increasing weight and age of the child
Limited evidence for older patients	There is insufficient evidence of the efficacy and safety of gene replacement therapy for patients with SMA types 1, 2, or 3, aged over 24 months (even with a body weight of up to 13.5 kg), or of any age but with a body weight of over 13.5 kg. Further research is needed to evaluate the benefits and risks of gene therapy in these populations
Anti-AAV9 antibody dosage	Prior to gene therapy administration, patients should undergo anti-AAV9 antibody dosage. The administration of gene therapy is contraindicated when the anti-AAV9 titer is greater than 1:50 measured within 30 days before the therapy
Corticosteroid treatment	Corticosteroid treatment should accompany gene therapy administration to reduce the risk of immune responses. A dosage of 1 to 2 mg/kg/day should be started one day before administration and maintained for at least 1 month, with a slow dose reduction over another month, or based on the transaminase levels
Laboratory monitoring: regular laboratory monitoring is crucial during gene therapy treatment	This includes complete blood count, coagulogram, renal function, transaminases, and troponin measurements before administration and at specific intervals during and after corticosteroid use
Persistent abnormalities in transaminase levels	If patients show persistent abnormalities in transaminase levels, further investigation, and prolonged use of corticotherapy may be required to prevent liver failure
Hepatologist evaluation	Patients who have elevated transaminases and do not adequately respond to corticosteroid treatment at a dose of 1 mg/kg/day should be promptly evaluated by a hepatologist.
Hospital administration	Gene therapy should be administered in a hospital environment capable of managing possible complications
Clinical stability and infections	Patients should be clinically stable in their general health prior to gene therapy infusion. Treatment should be delayed in patients with infections until the infection has resolved and the patient is clinically stable, for at least 2 weeks prior to infusion

Multidisciplinary care and disease-modifying therapies	The treatment of patients with SMA-5q should involve a combination of multidisciplinary care and disease-modifying therapies. This approach ensures comprehensive management and optimal outcomes for the patients
Key domains for monitoring	The follow-up of patients should focus on monitoring motor function, respiratory function, bulbar function (speech and swallowing), and nutrition. Regular assessments of these domains are essential to track the patient's progress and response to treatment
Use of clinical scales and assessment instruments	Clinical scales and other validated assessment instruments should be applied during follow-up to evaluate the response to drug therapies accurately.
Effective treatment outcomes	Treatment should be considered effective when there is improvement or stabilization in one or more of the monitored domains (motor, respiratory, nutritional, and bulbar)
Follow-up intervals	The follow-up intervals for patients with SMA-5q depend on the severity of their clinical condition. Patients with SMA type 1 should be followed up every 3-6 months on average, while patients with SMA types 2 and 3 should be followed up every 6 months on average
Discontinuation criteria for type 1 SMA	For children with SMA type 1, treatment discontinuation or replacement may be considered if there is a loss or lack of gain in motor and/or respiratory functions within an average period of 6 months of treatment. Motor and/or respiratory stabilization can also be considered a satisfactory outcome for those with a more chronic condition
Discontinuation criteria for types 2 and 3 SMA	For patients with SMA types 2 and 3, treatment discontinuation or replacement may be considered if there is functional loss or lack of disease stabilization detected within an average period of 12 months of follow-up
Switching therapy	Consider switching from one therapy to another if difficulties arise in applying intrathecal nusinersen due to worsening scoliosis, and if the patient experiences a treatment failure or lack of response to the current therapy
Combined therapies	The combined use of two or more modifying therapies in patients with SMA-5q has limited evidence in the medical literature regarding additional efficacy and safety. Thus, as of now, combination therapy for AME-5q is not recommended due to the limited data available

Genetic counseling for parents of SMA patients	A qualified professional should provide genetic counseling to the parents of patients diagnosed with SMA-5q. The purpose of counseling is to inform the parents about the genetic basis of the condition, the risk of recurrence in future pregnancies, and available testing options. Genetic testing, such as MLPA and/or gene sequencing, can be performed to identify heterozygous variants in the SMN1 gene in both parents to understand the risk of SMA-5q in future offspring
Genetic counseling for close relatives of SMA patients	Genetic counseling should also be offered to close relatives of SMA patients who may be at risk of being carriers of the SMN1 gene mutation. Identifying carriers within the family is important for understanding the risk of SMA-5q in other family members and providing appropriate counseling and testing options
Genetic counseling for potential partners of adult SMA patients	For adult patients with SMA-5q, genetic counseling should be provided to potential partners. This counseling aims to discuss the genetic implications of SMA-5q and the risk of having children with SMA-5q if both partners are carriers of the SMN1 gene mutation. MLPA testing and/or gene sequencing can be offered to potential partners to assess carrier status