Sometimes they come back: New and old spinal muscular atrophy adults in the era of nusinersen.

BACKGROUND AND PURPOSE: Following the commercial availability of nusinersen, there have been a number of new referrals of adults with spinal muscular atrophy (SMA) not regularly followed in tertiary-care centers or enrolled in any disease registry. METHODS: We compared demographics and disease characteristics, including assessment of motor and respiratory function, in regularly followed patients and newcomers subdivided according to the SMA type. RESULTS: The cohort included 166 adult patients (mean age: 37.09 years): one type I, 65 type II, 99 type III, and one type IV. Of these 166, there were 67 newcomers. There was no significant difference between newcomers and regularly followed patients in relation to age and disease duration. The Hammersmith Functional Motor Scale Expanded and Revised Upper Limb Module scores were higher in the regularly followed patients compared to newcomers in the whole cohort and in both SMA II and II. A difference was also found on ventilatory status (p = 0.013) and Cobb's angle >50° (p = 0.039) between the two subgroups. No difference was found in scoliosis surgery prevalence (p > 0.05). CONCLUSIONS: Our results showed differences between the two subgroups, even if less marked in the type III patients. In the type II patients, there was a higher proportion of newcomers who were in the severe end of the spectrum. Of the newcomers, only approximately a third initiated treatment, as opposed to the 51% in the regularly followed patients. The identification of patients who were not part of the registries will help to redefine the overall prevalence of SMA and the occurrence of different phenotypes.

Respiratory Trajectories in Type 2 and 3 Spinal Muscular Atrophy in the iSMAC Cohort Study.

OBJECTIVE: To describe the respiratory trajectories and their correlation with motor function in an international pediatric cohort of patients with type 2 and nonambulant type 3 spinal muscular atrophy (SMA). METHODS: This was an 8-year retrospective observational study of patients in the International SMA Consortium (iSMAc) natural history study. We retrieved anthropometrics, forced vital capacity (FVC) absolute, FVC percent predicted (FVC%P), and noninvasive ventilation (NIV) requirement. Hammersmith Functional Motor Scale (HFMS) and revised Performance of Upper Limb (RULM) scores were correlated with respiratory function. We excluded patients in interventional clinical trials and on nusinersen commercial therapy. RESULTS: There were 437 patients with SMA: 348 with type 2 and 89 with nonambulant type 3. Mean age at first visit was 6.9 (±4.4) and 11.1 (±4) years. In SMA type 2, FVC%P declined by 4.2%/y from 5 to 13 years, followed by a slower decline (1.0%/y). In type 3, FVC%P declined by 6.3%/y between 8 and 13 years, followed by a slower decline (0.9%/y). Thirty-nine percent with SMA type 2% and 9% with type 3 required NIV at a median age 5.0 (1.8-16.6) and 15.1 (13.8-16.3) years. Eighty-four percent with SMA type 2% and 80% with type 3 had scoliosis; 54% and 46% required surgery, which did not significantly affect respiratory decline. FVC%P positively correlated with HFMS and RULM scores in both subtypes. CONCLUSIONS: In SMA type 2 and nonambulant type 3, lung function declines differently, with a common leveling after age 13 years. Lung and motor function correlated in both subtypes. Our data further define the milder SMA phenotypes and provide information to benchmark the long-term efficacy of new treatments for SMA.

Síndrome de Werdnig-Hoffmann / Werdnig-Hoffmann disease

Introducción: El síndrome de Werdnig-Hoffmann o atrofia espinal tipo I forma parte de las atrofias musculares espinales y es la más grave de las tres formas clínicas existentes. Tiene carácter hereditario autosómico recesivo, no tiene tratamiento, es de carácter progresivo y por lo general culmina con la muerte del paciente entre el primero y segundo año de vida. Objetivo: Describir la conducta de la vía respiratoria anatómicamente difícil conocida en un paciente con síndrome de Werdnig-Hoffmann operado de litiasis renal derecha. Caso clínico: Paciente masculino de 39 años de edad, nivel de escolaridad superior, con diagnóstico de litiasis obstructiva en riñón derecho, propuesto para realizar una nefrolitotomía percutánea. Los exámenes en la consulta de anestesia diagnosticaron una vía respiratoria anatómicamente difícil. Pese a contar con la colaboración del paciente, personal entrenado, equipamiento necesario y proceder según los algoritmos recomendados en la literatura, se necesitó una vía quirúrgica para realizar la operación. Se efectúo el proceder quirúrgico propuesto sin complicación y el paciente salió del quirófano despierto y consiente. Conclusión: De requerirse otra intervención quirúrgica, sería necesario iniciar la intubación mediante fibroscopía óptica para evitar el edema de las vías respiratorias. De no obtenerse una vía respiratoria segura por este método, el paciente precisaría una vía aérea quirúrgica(AU)

Introduction: Werdnig-Hoffmann disease or spinal atrophy type I is part of the spinal muscular atrophies and the most serious of the three clinical forms in existence. It is an autosomal recessive hereditary condition, with no treatment, progressive in nature and usually culminates with the death of the patient between the first and second year of life. Objective: To describe the behavior of the anatomically difficult airway identified in a patient with Werdnig-Hoffmann disease operated for right renal lithiasis. Clinical case: Male patient at age 39, higher education level, with a diagnosis of obstructive lithiasis in the right kidney, proposed to be performed a percutaneous nephrolithotomy. The exams in the anesthesia consultation provided diagnosis of an anatomically difficult airway. Despite having the cooperation of the patient, trained personnel, necessary equipment and proceeding according to the algorithms recommended in the literature, a surgical approach was needed to perform the operation. The proposed surgical procedure was carried out without complications and the patient left the operating room awake and conscious. Conclusion: In case that another surgical intervention is required, it would be necessary to initiate intubation by optical fibroscopy in order to avoid edema of the respiratory tract. In case a safe airway is not obtained by this method, the patient would need a surgical airway(AU)

[Hirayama disease in paediatrics: a clinical case report and review of the literature]. / Enfermedad de Hirayama en pediatría: aportación de un caso clínico y revisión de la bibliografía.

INTRODUCTION: Hirayama disease is a rare children's muscular atrophy that affects young Asian males, with muscular atrophy usually in one of the upper limbs that progresses slowly and later stabilises. It is diagnosed by means of electromyographic/electroneurographic with conduction speed studies (EMG/ENG-CS) and by magnetic resonance imaging (MRI) of the spinal cord in a neutral position and with cervical flexion. Treatment is based on the cervical collar and surgery (severe cases). Very few studies have been conducted on patients at the paediatric age. CASE REPORT: We report the case of a 7-year-old girl with atrophy of the muscles of the left hand and forearm, and a disease history of two years. The EMG/ENG-CS scans presented signs of very severe chronic denervation in the myotomes of C7, C8 and T1 on the left side, with conservation of the amplitudes of sensory evoked potentials, consistent with cervical myelopathy. Results of an MRI scan of the cervical spinal cord in a neutral position were normal at that level. Later, owing to suspicions pointing towards Hirayama disease, a new MRI scan of the cervical spinal cord was performed in a neutral position and in flexion. This second scan showed asymmetry in the size and morphology of the anterior funiculi of the spinal cord at C6/C7, hypersignal in the homolateral anterior horn and ingurgitation of the posterior epidural venous plexus. With a diagnosis of Hirayama disease, treatment is started with a cervical collar in order to prevent the damage from getting worse. CONCLUSIONS: This case of Hirayama disease is peculiar due to its epidemiological characteristics and is presented here with the aim of making this entity more widely known in our milieu. If diagnosed at an early stage, treatment is effective, and the studies conducted on children at the paediatric age are reviewed.

TITLE: Enfermedad de Hirayama en pediatria: aportacion de un caso clinico y revision de la bibliografia.Introduccion. La enfermedad de Hirayama es una rara atrofia muscular juvenil que afecta a varones jovenes de origen asiatico, con atrofia muscular habitualmente de una de las extremidades superiores de progresion lenta con estabilizacion posterior. Se diagnostica por estudios electromiograficos/electroneurograficos con velocidad de conduccion (EMG/ENG-VC), y por resonancia magnetica (RM) medular en posicion neutra y en flexion cervical. El tratamiento se basa en el collarin cervical y cirugia (casos graves). Son muy pocos los estudios realizados en edad pediatrica. Caso clinico. Niña de 7 años, con atrofia de la musculatura de la mano y el antebrazo izquierdos, de dos años de evolucion. En EMG/ENG-VC presenta signos de denervacion cronica muy grave en los miotomos correspondientes a C7, C8 y D1 izquierdos, con conservacion de amplitudes de potenciales sensitivos evocados, congruentes con mielopatia cervical. La RM medular cervical en posicion neutra muestra un resultado normal en ese nivel. Posteriormente, por la sospecha dirigida de enfermedad de Hirayama, se realiza una nueva RM medular cervical en posicion neutra y en flexion, que muestra asimetria en el tamaño y morfologia de los cordones anteriores medulares en C6/C7, hiperseñal en el asta anterior homolateral e ingurgitacion del plexo venoso epidural posterior. Con el diagnostico de enfermedad de Hirayama se inicia tratamiento con collarin cervical para evitar la progresion del daño. Conclusiones. Se presenta un caso de enfermedad de Hirayama peculiar por las caracteristicas epidemiologicas, con la finalidad de difundir esta entidad en nuestro medio, cuyo diagnostico precoz permite un tratamiento eficaz, y se revisan los estudios realizados en edad pediatrica.

Recommendations for the diagnosis and management of typical childhood spinal muscular atrophy.

Typical childhood spinal muscular atrophy is a disease that affects the anterior horn of the spinal cord related to SMN1 gene defects. Since no etiological treatment is currently available, its management is necessarily symptomatic and involves multidisciplinary care. The national plan on rare diseases for 2005-2008 developed by the French Ministry of Health resulted in the creation of 12 reference centres for neuromuscular diseases, mainly to improve their diagnosis and management. During the first one-day clinical research meeting on neuromuscular disorders, organized by the French Association to fight myopathies (AFM) in May 2007, clinicians from the 12 national reference centers led workshops for each of the main neuromuscular diseases. Concerning spinal muscular atrophy, discussions involving specialists from medical and allied professions were led by clinicians in charge of the workshop sessions. This paper reports the final version of their recommendation regarding the diagnosis, monitoring and management of typical infantile spinal muscular atrophy, which is necessarily multidisciplinary, including orthopedic, pulmonary, gastroenterology and nutrition care.

A cohort study of children and young people with progressive neuromuscular disorders: clinical and demographic profiles and changing patterns of referral for palliative care.

BACKGROUND: Progressive neuromuscular disease in children is life limiting and these children and young people would benefit from palliative care services, but data are limited on the number and demography of these children. AIM: To describe the clinical and demographic profile of children referred to a Children's hospice in the UK with progressive neuromuscular disease. SETTING/PARTICIPANTS: All children and young people with progressive neuromuscular disorders referred to Martin House Children's Hospice between 1987 and 2010. DESIGN: Retrospective cohort study. RESULTS: 300 children with progressive neuromuscular disease were referred to the hospice. Seventy percent (210) of these children had Duchenne Muscular Dystrophy, 22% (67) had Spinal Muscular Atrophy (34 with Type I) and 8% had other neuromuscular diseases. Numbers of referrals have not significantly increased over the last 15 years, although an increasing number come from a South Asian background (from 4% to 32%) and a higher number of children have conditions other than Duchenne Muscular Dystrophy. A total of 55.3% (166) of all referrals came from areas of the highest deprivation. Survival patterns varied by diagnostic group, but ethnicity and deprivation were not associated with survival in these children. CONCLUSIONS: The profile of children with progressive neuromuscular conditions who were referred for palliative care has changed over the last 20 years, with a different spectrum of underlying diagnoses and a greater number from a South Asian background. The higher than expected proportion of children living in areas of high deprivation has been consistent over time.

Descriptive epidemiology of spinal muscular atrophy type I in Estonia.

Spinal muscular atrophy is the second most frequent autosomal-recessive disorder in Europeans. There are no published epidemiological data on SMA in Estonia and other Baltic countries. The aim of this study was to estimate the incidence of SMA I in Estonia. All patients with SMA I diagnosed between January 1994 and December 2003 were included in the study. The diagnosis was established on the basis of neurological evaluation, ENMG findings, molecular studies and muscle biopsy. PCR and restriction enzyme analysis was used to detect the homozygous deletion of the SMN1 gene. A total of 9 cases of SMA I were identified during this 10-year period. The incidence of SMA I in Estonia is 1 in 14,400 live births, which is similar to the result from Hungary but lower than average incidence in the world. Only one of the patients was female. Typical SMN1 gene deletion was found in all cases.

SMN1 deletions among singaporean patients with spinal muscular atrophy.

INTRODUCTION: Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disorder characterised by degeneration of spinal cord anterior horn cells, leading to muscular atrophy. It is the second most frequent autosomal recessive disease among Caucasian populations with a prevalence of between 1 in 6000 and 1 in 10,000 live births, and a carrier frequency of about 1 in 50. The International SMA Consortium classification defines several types of SMA depending on the age of onset and clinical severity. In the past, the diagnosis of SMA was confirmed by muscle biopsy and, sometimes, electromyography. In 1990, SMA was linked to the 5q13 region of chromosome 5. In 1995, it was found that >95% of patients with SMA have homozygous deletions of exons 7 and 8 of the survival motor neurone 1 (SMN1) gene, one of the candidate genes identified within 5q13. The purpose of our study was to determine the frequency of SMN1 deletions in patients with known SMA and the impact of this on the diagnosis of SMA. MATERIALS AND METHODS: Molecular analysis was performed on stored DNA and case notes were reviewed retrospectively. RESULTS: Twenty-two (91.7%) out of 24 patients with all types of SMA were homozygously deleted for exons 7 and/or 8 of SMN1. We also report our experience with prenatal diagnosis of SMA. CONCLUSIONS: Molecular studies can replace conventional investigations for SMA and have made the option of prenatal diagnosis possible for couples at risk.

Pulmonary function and scoliosis in children with spinal muscular atrophy types II and III.

AIMS: The objectives were to evaluate the clinical course of spinal muscular atrophy (SMA) types II and III patients necessitating scoliosis surgery at the National University Hospital, Singapore. METHODS: A retrospective review of SMA types II and III patients, born over a 10-year period between 1983 and 1992, was conducted. RESULTS: There were eight patients: four with SMA type II and four with SMA type III. The mean age at scoliosis surgery was 9 years 7 months (range 7 years 6 months-12 years 4 months). The mean preoperative Cobb angle was 65.4 degrees (range 43-90 degrees ) and the mean postoperative Cobb angle was 22.6 degrees (range 12-45 degrees ), with a mean correction of 64.8% (range 47.7-77.8%). The decline in percentage predicted forced vital capacity (FVC) was 7.7% (95% CI: 12.4% to 3.0%) per year preoperatively and this was reduced to 3.8% (95% CI: 5.8% to 1.9%) per year postoperatively. The mean length of preoperative and postoperative lung function follow-up was 6.3 months (range 0.03-31 months) and 44 months (range 0-110 months), respectively. CONCLUSIONS: This study suggests that pulmonary function in SMA types II and III continues to decline after scoliosis surgery, though the rate of decline is less marked. Overall, the combined results from this study and all other previously published studies are conflicting in regard to the effect of scoliosis surgery on pulmonary function in SMA types II and III, though half of the studies (3 of 6) did demonstrate a continued decline in lung function postoperatively. This decline in pulmonary function despite spinal stabilization is likely secondary to the progressive neuromuscular weakness of the disease.

Hip dislocation in patients with spinal muscular atrophy.

The propensity for hip dislocation in patients with spinal muscular atrophy (SMA) is well documented, but the appropriate treatment and even the long-term outcome of these hips in this patient population have not been well defined. The purpose of this study was to determine by long-term follow-up the natural history of dislocated hips in a cohort of SMA patients from a single institution. Pain and functional difficulties (positioning, skin and perineal care) were assessed and radiographs were reviewed in a total of 41 patients with a mean of 18 years of follow-up. Seventeen of 82 hips (21%) were dislocated in 14 patients and 20 hips were subluxed. Only two patients had any hip pain at follow-up, one had difficulty with seating, and no patients had difficulty with perineal care. Given the small number of patients with symptoms with dislocated hips, observation rather than surgical intervention seems warranted in SMA patients with hip dislocation.

Molecular genetic analyses of five Vietnamese patients with spinal muscular atrophy.

Most patients with spinal muscular atrophy (SMA) have been reported to show homozygous deletion of the gene responsible for SMA, SMN1. However, whether SMA patients homozygous for the SMN1 deletion exist in Southeast Asian countries, including Vietnam, remains to be determined, because molecular genetic analyses of SMA patients from these countries have not been reported. In this preliminary study, we analyzed five Vietnamese SMA patients and found that SMN1 gene exons 7 and 8 were completely absent in one of them, a 6-month-old girl with hypotonic muscles. Thus, SMN1 deletion can be a cause of SMA in Vietnam, although other genetic abnormalities should be considered as etiological factors in many cases. In conclusion, we identified a homozygous deletion of the SMN1 gene in a Vietnamese SMA patient. Since the number of the patients analyzed in this study was very limited, it is too early to determine whether SMN1 deletion is not a main cause of SMA in Vietnam.

Spinal muscular atrophy. Incidence in Iceland.

Spinal muscular atrophy (SMA) is among the commonest degenerative disorders of the nervous system in childhood. This is an inherited autosomal recessive disease which results in premature death of anterior horn cells of the spinal cord and is manifested by progressive weakness and atrophy of skeletal muscles. Few studies have looked at the frequency of the disease in a defined population. We identified all patients diagnosed with SMA in Iceland during a 15-year period. The diagnosis is based on typical symptoms and supported by results of electromyography/nerve conduction studies and muscle biopsy. The average annual incidence was 13.7 per 100,000 live births for all types of SMA, which is similar to that reported in other population-based studies.

[Werdnig-Hoffmann disease. The first prenatal diagnosis in Cuba]. / Enfermedad de Werdnig-Hoffmann. Primer diagnóstico prenatal en Cuba.

INTRODUCTION: Spinal muscular atrophy (SMA) is an autosomal recessive disorder characterized by the degeneration of cells of the spinal cord. The gene was localized on chromosome 5q13 and exists in two almost identical forms, which are distinguished by the change of base on exones 7 and 8. Mutations of the gene of survival motoreneuron (SMN) are the cause of illness. CLINICAL CASE: We report, for the first time in Cuba, the prenatal diagnosis of a type II SMA carrier, using molecular methods for direct detection of the mutation on exones 7 and 8 of the SMN gene, and haplo-identification with microsatellite markers of chromosome 5q as an indirect method. A sample of amniotic liquid was taken at 18 weeks of gestation and the DNA extracted. No deletions were detected on exones 7 and 8 of the foetal DNA, which was therefore normal. CONCLUSIONS: Detection of deletions on the SMN gene is a method which permits detection of the condition (healthy or unhealthy) of the foetus, quickly and reliably, without requiring investigation of the entire family to obtain a result. The method does not require radio-active PCR, the results are clear and precise and may be obtained within 24 hours. It may also take the place of invasive methods such as muscle biopsy and electro-myography and contribute to genetic assessment in families in which there is no DNA of the affected child.

A clinical study of childhood spinal muscular atrophy in Sicily: a review of 75 cases.

The aim of this study is to evaluate 75 patients affected by childhood-onset spinal muscular atrophy (SMA), using the diagnostic criteria and classification recently suggested by the International SMA Collaboration Consortium. Sex predominance, age of onset, clinical evaluation and other relevant clinical data of the disease are reported. These findings, as well as the role of the EMG and muscle biopsy as diagnostic tools, are discussed. The study suggests that the frequency of SMA in some areas of Sicily is high, possibly correlating with a relatively high gene frequency.