Spinal muscular atrophy (SMA) is an autosomal recessive motor neuron disease with a high incidence and is the most common genetic cause of infant mortality. It is characterized by degeneration of the spinal motor neurons, which results in progressive muscle weakness and atrophy and, in severe cases, respiratory failure and death. The causal gene is the survival motor neuron (SMN1) gene on 5q13, even if different genes are associated to proximal non-5q forms of SMA. Diagnosis is based on history, clinical examination and electromyography (EMG) and can be confirmed by genetic testing. Timing of diagnosis is crucial for SMA because early diagnosis may lead to early supportive care and reduction of patient and caregiver burden. We describe a case of SMA presenting with hypotonia and complicated by an infection of the lower respiratory tract, which was promptly suspected and diagnosed by clinicians.
A 13-month-old boy born at 39 weeks gestation presented to our Department for generalized hypotonia and reduced antigravity movements in the lower limbs observed since he was 6-month-old.
Parents were consanguineous. (Fig. 1) No decrease in foetal movement was reported. Family history was negative for neuromuscular disorders or sudden death syndrome.
The mother was 6 months pregnant of a girl. Physiologic history showed an overall marked delay in the acquisition of postural stages.
On physical examination, the child appeared well. There were no dysmorphic features. A generalized hypotonia was evident at the ventral suspension. The ability to maintain head control and the sitting posture with support was present. Cranial nerves were normal. Antigravity movements were present in the upper limbs, but not in the lower limbs. Deep tendon reflexes were absent. Sensibility was normal. A tendency to diaphragmatic breathing was present.
Fig. 1 Genealogical tree
Blood chemistry investigations showed normal parameters. Creatine phosphokinase (CPK) serum level was normal too. SMA was suspected and EMG was performed, revealing neurogenic pattern compatible with active and chronic denervetion with fibrillation and positive sharp waves at rest on proximal and distal muscles. The diagnosis was confirmed by the SMN gene deletion test which showed the classic mutation of the SMN1 gene.
During the hospitalization, the patient had pneumonia, with fever (max 39, 5 °C), dyspnea and increase of white blood cells (WBC 29010 mmc, N 80%, L 10%) and inflammatory markers. Chest X-ray showed pulmonary condensation in the right basal lung field. Intravenous antibiotic therapy (ceftriaxone 90 mg/kg/die) was soon started with a gradual improvement of clinical conditions. As soon as the diagnosis of SMA was confirmed, genetic counseling was offered to the patient and his family and they were directed to the nearest reference center for follow-up of neuromuscular disease, to receive the necessary treatments and support. Early diagnosis also allowed us to make prenatal diagnosis by amniocentesis, which ruled out any mutation on the fetus.
Inherited SMA was first recognized as a distinct disease entity with a spinal nature at the end of the 19th century (1, 2) . This neuromuscular disease is the leading genetic cause of infantile mortality and the second most common fatal autosomal-recessive disorder after cystic fibrosis (3), with an estimated incidence of 1 in 6000 to 1 in 11, 000 live births in the United States with a high carrier frequency of 1 in 40 to 60. (4-7) The disease is characterized by progressive symmetrical muscle weakness deriving from the degeneration and loss of alpha motor neurons in the spinal cord. Childhood SMA is subdivided into four clinical groups on the basis of age of onset and clinical course (8, 9), even if it should be recognized than the disorder demonstrates a continuous range of severity. Type I SMA (Werdnig-Hoffman disease) is the most severe and frequent form of SMA, representing 60% up to 70% of cases (10) . It is characterized by severe and generalized hypotonia and muscle weakness before 6 months of age and death from respiratory failure usually occurs within the first 2 years. Type II SMA is the intermediate form of the disease with onset prior to 18 months of age. Children are able to sit but never gain the ability to walk. Prognosis in this group is largely dependent on the degree of respiratory involvement. Type III SMA (Kugelberg-Welander disease) is the mild form characterized by onset after 18 months of age. Patients learn to walk unaided and have prolonged survivals. Type III SMA is further subdivided into two subgroup, IIIa (onset before 3 years) and IIIb (onset after 3 years) . Type IV SMA and it is also known as proximal adult-type SMA since the first symptoms present at the age of 20 to 30 years. In most cases SMA can be considered a purely autosomal recessive condition caused by the homozygous deletion of Survival Motor Neuron-1 (SMN1) gene on chr5q13, which was identified as the causal gene 20 years ago. (11) Humans have two copies of SMN gene located on chromo¬some 5q13 that are identified as SMN1 (telomeric) and SMN2 (centromeric) (11), that is almost identical to the SMN1 gene but encode a truncated, dysfunctional SMN protein due to its defective splicing pattern. (Fig.2) .
Fig.2 Molecular basis of SMA
The severity of the SMA phenotype inversely correlates with the SMN2 copy number and the level of full-length SMN protein produced by SMN2, therefore SMN2 is the primary disease-modifying gene in humans. (12) Low levels of SMN protein result in the degeneration of spinal motor neurons and cause muscle weak¬ness that is followed by symmetric limb paralysis, respiratory failure, and death. Recent developments in next generation sequencing technologies, however, have discovered a growing number of clinical conditions called as non-5q forms of spinal muscular atrophy which seem to be unlinked to chr5q13 and represent a small proportion (4%) of SMA patients with high phenotypic variability and various inheritance patterns. (13, 14) The diagnosis of SMA is based on history and clinical examination and can be confirmed by genetic testing. The clinical hallmark of SMA is muscle weakness, more pronounced for proximal than distal limb muscles and generally affecting the legs more than the arms. The clinical course ranges from static to rapidly progressive, leading to respiratory distress requiring mechanical ventilation. Sensitivity is spared, while deep tendon reflexes can vary from absent to weak, depending on form, age at onset and duration of the disease. In most cases intellect is normal. (4) An important early step is to differentiate motor neuron disease from other disorders with similar clinical features. The most important differential diagnostic conditions for a child presenting with hypotonia and weakness are congenital myopathies and muscular dystrophies, congenital myotonic dystrophy, congenital myasthenic syndromes, metabolic myopathies, congenital disorders of the motor neuron and the peripheral nerve (congenital hypomyelinating neuropathy), as well as non-neuromuscular conditions, including neonatal sepsis, acute hypoxic ischaemic encefalopathy and diskynetic ore metabolic patterns. If history and neurological examination are suggestive of motor neuron disease, many tests may be performed at a second stage, such as laboratory exams (including serum creatine phosphokinase levels) and electrophysiological tests, such as electromyography and nerve conduction studies. In the case of motor unit involvement, genetic testing of SMN1 need to be pursued first, to individuate or exclude SMN1 deletions or point mutations, then other motor neuron disorders such as non-5q SMA should be investigated. (4, 14) Prenatal diagnosis is possible through molecular analysis of amniocytes or chorionic villus samples. A systematic literature search carried out in 2015 by Lin et al. showed that diagnostic delay is common in SMA and that the length of delay varied by severity and type of disease, since the shortest delay in diagnosis was observed for SMA type I patients and the longest delay was for type III patients, underlying that severity of disease has an impact on time to diagnosis. (16) A later diagnosis may result in a missed opportunity for optimal early intervention for SMA. At present, treatment is symptomatic and is based on multidisciplinary approaches in order to improve the quality of life. (17) Physiotherapy and occupational and respiratory therapies are necessary. Non-invasive ventilation and gastrostomy may be useful. Antibiotic therapy is used in the presence of lung infections as complication of disease. Patients may need a wheelchair or back support corsets, and surgical options are often chosen for scoliosis, joint symptoms, related to lack of mobility. New treatments based on increasing the expression of full-length SMN protein levels from the SMN2 gene are being investigated through clinical trials. (18)
Spinal muscular atrophy is a neuromuscular disorder of pediatric interest which has no cure yet and need a multidisciplinary diagnostic and therapeutic approach in order to slow muscle atrophy and preserve essential life function such as swallowing, breathing and locomotion. The various pattern of symptoms and the lack of expertise in this area for many healthcare professionals lead to a frequent diagnostic delay of SMA, even if awareness of SMA is recently increasing. The diagnostic “odyssey” from the time first symptoms are noticed to a confirmed genetic diagnosis of SMA puts patients and caregivers through physical and mental stress and deny the possibility of early intervention. In this work we present a case of SMA early recognized and diagnosed since a detailed clinical and neurological examination and underline the importance of a correct diagnostic approach in order to ensure disease issues to a specific follow up route.
- Hoffmann J. Ueber chronische spinale Muskelatrophie im Kindesalter auf familiarer Basis. Stch Z Nervenheilkd 1893;3:427
- Werdnig G. Two early infantile hereditary cases of progressive muscular atrophy simulating dystrophy, but on a neural basis. Arch f Psychiat 1981; 22:706.
- Lunn MR, Wang CH. Spinal muscular atrophy. Lancet 2008; 371:2120-2133
- D’Amico A, Mercuri E, Tiziano FD, Bertini E. Spinal muscular atrophy. Orphanet J Rare Dis. 2011;6:71.
- Prior TW, Snyder PJ, Rink BD, et al. Newborn and carrier screening for spinal muscular atrophy. Am J Med Genet A. 2010; 152A: 1608-1616.
- Mercuri E, Bertini E, Ianaccone ST. Childhood spinal muscular atrophy: controversies and challenges. Lancet Neurol. 2012; 11: 443-452.
- Sugarman EA, Nagan N, Zhu H, et al. Pan-ethic carrier screening and prenatal diagnosis for spinal muscular atrophy: clinical laboratory analysis of > 72, 400 specimens. Eur J Hum Genet. 2012; 20:27-32
- Zerres K, Rudnik-Schöneborn S. Natural history in proximal spinal muscular atrophy. Clinical analysis of 445 patients and suggestions for a modification of existing classifications. Arch Neurol 1995; 52
- Munstat TL, Davies KE. International SMA consortium meeting. Neuromuscul Disord 1992; 2: 423-428.
- Meldrum C, Scott C, Swoboda KJ. Spinal muscular atrophy genetic counseling access and genetic knowledge: parents perspective. J Child Neurol 2007; 22: 1019-1026.
- Lefebvre S, Bürglen L, Reboullet S, Clermont O, Burlet P, Viollet L, et al. Identification and characterizationof a spinal muscular atrophy-determining gene. Cell 1995; 80 (1):155–165.
- Feldkotter M, Schwarzer V, et al. Quantitative analyses of SMN1 and SMN2 based on real-time linghtCycler PCR: fast and highly reliable carrier testing and prediction of severity of spinal muscular atrophy. Am J Hum Genet 2002;70:358-368.
- Wirth B. An update of the mutation spectrum of the survival motor neuron gene (SMN1) in autosomal recessive spinal muscular atrophy (SMA). Hum Mutat 2000;15:228-37.
- Peeters K, Chamova T, et al. Clinical and genetic diversity of SMN1-negative proximal spinal muscular atrophies. Brain 2014;137:2879-2896.
- Baumer D, Talbot K, Turner MR. Advances in motor neuron disease. J R Soc Med 2014; 107:14-21
- Lin CW, Kalb STJ, Yeh WS. Delay in diagnosis of Spinal Muscular Atrophy: a systematic literature review. Pediatr Neurol 2015; 53:293-300.
- Iannaccone ST. Modern management of spinal muscular atrophy. J Child Neurol 2001; 98:9808-9813
- Prior TW. Perspectives and diagnostic considerations in spinal muscular atrophy. Genet Med 2010;12 (3):145-152