History

Fact Explanation
Introduction to the disease It is an autosomal recessive disease which causes degeneration and loss of the anterior horn cells in the spinal cord as well as the brain stem nuclei. This ultimately results progressive muscle weakness. In distal spinal muscular atrophy, so called SMA IV the onset of disease is usually in the second or third decade of life.[1].
Muscle weakness It is a characteristic feature of the disease.Progressive degeneration and loss of the anterior horn cells in the spinal cord as well as the brain stem nuclei will give rise to above manifestation. Almost always the weakness is symmetric and progressive. However in distal spinal muscular atrophy the initial weakness and wasting is seen in distal muscles, followed by weakness of other muscle groups.The weakness begins in their second or third decade of life.[1].
Muscle wasting wasting is initially seen in distal muscles, then it spread in to other muscle groups.[1].
Gait disturbances Findings of SMA IV are similar to the findings of SMA III. Affected individuals experience gait disturbances in their second or third decades of life.[1].
Muscle pain/cramps Muscle cramps and pains are experienced by the affected patients. But it has not been adequately studied.[1],[3].
Dysphonia Seen in certain patients due to vocal cord paralysis. Progressive bulbar paralysis causing multiple cranial nerve palsies will leads to above manifestation.[2].
Facial diplegia Progressive bulbar paralysis causing multiple cranial nerve palsies in distal SMA causes bilateral facial weakness.[1],[2].
Respiratory failure Not Usually a complication of distal spinal muscular atrophy. If occurs, it will be in late adulthood.[1],[4].
Joint contractures Not a common complication as other forms of SMA. Can be seen in affected patients in their adulthood.[1],[4].
Scoliosis Recognized complication among SMA affected individuals. It is a major problem among most persons with SMA II as well as half of the patients with SMA III rather than in distal spinal muscular atrophy.[1].
Obesity Another complication encountered by affected individuals in their adulthood. Lack of energy requirement due to muscle weakness with preserved appetite can leads to this condition.[1],[4].
Epilepsy SMA IV associated with progressive myoclonic epilepsy is an atypical finding encountered in some affected individuals.[5].
Family history of SMA Spinal muscular atrophy is inherited in an autosomal recessive manner so that having a positive family history increase the risk of developing SMA.[1]
References
  1. PRIOR TW, RUSSMAN BS, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Spinal Muscular Atrophy [online] 1993 [viewed 26 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301526
  2. PRIDMORE C, BARAITSER M, BRETT EM, HARDING AE. Distal spinal muscular atrophy with vocal cord paralysis. J Med Genet [online] 1992 Mar, 29(3):197-199 [viewed 26 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1015897
  3. PENTTILä SINI, JOKELA MANU, HACKMAN PETER, MAIJA SAUKKONEN ANNA, TOIVANEN JARI, UDD BJARNE. Autosomal dominant late-onset spinal motor neuronopathy is linked to a new locus on chromosome 22q11.2-q13.2. Eur J Hum Genet [online] December, 20(11):1193-1196 [viewed 30 October 2014] Available from: doi:10.1038/ejhg.2012.76
  4. D'AMICO A, MERCURI E, TIZIANO FD, BERTINI E. Spinal muscular atrophy Orphanet J Rare Dis [online] :71 [viewed 30 October 2014] Available from: doi:10.1186/1750-1172-6-71
  5. LIYANAGE DS, PATHBERIYA LS, GOONERATNE IK, VITHANAGE KK, GAMAGE R. Association of type IV spinal muscular atrophy (SMA) with myoclonic epilepsy within a single family Int Arch Med [online] , 7(1):42 [viewed 30 October 2014] Available from: doi:10.1186/1755-7682-7-42

Examination

Fact Explanation
Postural tremor of the fingers Initial inspection finding of affected individuals.[1].
Muscle atrophy Seen among affected individuals due to lower motor nerve involvement. Progressive degeneration and loss of the anterior horn cells in the spinal cord as well as brain stem nuclei giving rise to this manifestation.[1].
Muscle weakness Another classic finding of the disease due to lower motor nerve involvement. It is a symmetrical and progressive weakness. Seen in second or third decades in their life. [1].
Tongue fasciculation A manifestation due to bulbar involvement. not seen in all the affected individuals.[1].
Dysarthria and hoarseness. It is a recognized finding .Progressive bulbar paralysis causing palatal and vocal cord palsies, and tongue involvement may give rise to this manifestation.[2].
Bilateral facial weakness Cranial nerve examination finding in distal SMA. progressive bulbar paralysis causing multiple cranial nerve palsies will leads to this manifestation.[2].
Ophthalmoplegia Another atypical cranial nerve finding seen in some patients due to oculomotor nerve palsy.[1],[3].
Higher functions examination findings .They have normal higher functions. There is no memory or intellectual impairment seen in affected individuals.[1].
Sensory nerve system examination findings There is no detectable sensory impairment in affected individuals.[1]
References
  1. PRIOR TW, RUSSMAN BS, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Spinal Muscular Atrophy [online] 1993 [viewed 26 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301526
  2. PRIDMORE C, BARAITSER M, BRETT EM, HARDING AE. Distal spinal muscular atrophy with vocal cord paralysis. J Med Genet [online] 1992 Mar, 29(3):197-199 [viewed 26 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1015897
  3. LIYANAGE DS, PATHBERIYA LS, GOONERATNE IK, VITHANAGE KK, GAMAGE R. Association of type IV spinal muscular atrophy (SMA) with myoclonic epilepsy within a single family Int Arch Med [online] , 7(1):42 [viewed 30 October 2014] Available from: doi:10.1186/1755-7682-7-42

Differential Diagnoses

Fact Explanation
Motor neurone disease It is a progressive neurodegenerative disease of unknown etiology. There are forms of motor neuron disease that affect selectively either upper motor neurons ( pure upper motor neuron syndrome/primary lateral sclerosis) or lower motor neurons.(Pure lower motor neuron syndrome/progressive muscular atrophy). Combination of both is named as ALS.[1]. The lower motor neuron involvement in disease can cause LMN manifestations such as fasciculation, atrophy, weakness, and hyporeflexia, Upper motor neurone involvement will cause UMN symptoms and signs such as spasticity, weakness and hyperreflexia where the progressive bulbar involvement causes bulbar symptoms such as dysarthria and dysphagia.[2],[3].
Glycogen Storage Disease Type II Classic infantile-onset disease may present with features such as generalized muscle weakness, hypotonia, , cardiomegaly as well as hypertrophic cardiomyopathy,.They may also present with feeding difficulties, failure to thrive, respiratory distress, and hearing loss. Non-classic variant of infantile-onset disease may present with slowly progressive muscle weakness, motor development delay,and they may died due to respiratory failure in early childhood. Late-onset disease may present with respiratory insufficiency; clinically significant cardiac involvement as well as with characteristic proximal muscle weakness.[4].
Myasthenia gravis (MG) It is an autoimmune disease. It causes binding of autoantibodies to proteins involved in signaling at the neuromuscular junction thereby developing failure of neuromuscular transmission. There are congenital as well as acquired forms of MG.Muscle weakness that worsens after use of affected muscles is a characteristic finding of the disease.Extrinsic ocular muscles involvement in initial course of disease is seen about two-thirds of patients. Bulbar and limb muscles get involved with the progression of disease.[5].
Congenital muscular dystrophy It is a clinically and genetically heterogeneous group of inherited muscle disorders. They may present with muscle weakness in early infancy. Low muscle tone and poor spontaneous movements leads to the appearance of floppy infant Joint and spinal rigidity as well as delayed motor milestones can be recognized. Intellectual disability ranging from mild to severe can be identified in some affected individuals.[6].
X-linked spinal and bulbar muscular atrophy It is also called as Kennedy disease. It is a gradually progressive neuromuscular disorder in adult men.Proximal muscle weakness, muscle atrophy, and fasciculations may resulted due to degeneration of lower motor neurons.Androgen insensitivity in affected individuals may leads to development of features such as gynecomastia, testicular atrophy, as well as reduced fertility.[7].
Spinal muscular atrophy and respiratory distress (SMARD) There are three distinct groups. Some individuals may present with congenital respiratory failure with congenital contractures whereas the others may present with respiratory distress after age six months without congenital contractures. Some affected individuals may develop respiratory distress with onset between ages six weeks and six months with minimal or no movement of the distal muscle groups.[7].
References
  1. TALBOT K. Motor neurone disease Postgrad Med J [online] 2002 Sep, 78(923):513-519 [viewed 26 October 2014] Available from: doi:10.1136/pmj.78.923.513
  2. HOWARD R S. Management of motor neurone disease. [online] 2002 December, 78(926):736-741 [viewed 26 October 2014] Available from: doi:10.1136/pmj.78.926.736
  3. KüHNLEIN PETER, GDYNIA HANS-JüRGEN, SPERFELD ANNE-DORTE, LINDNER-PFLEGHAR BEATE, LUDOLPH ALBERT CHRISTIAN, PROSIEGEL MARIO, RIECKER AXEL. Diagnosis and treatment of bulbar symptoms in amyotrophic lateral sclerosis. Nat Clin Pract Neurol [online] December, 4(7):366-374 [viewed 26 October 2014] Available from: doi:10.1038/ncpneuro0853
  4. LESLIE N, TINKLE BT, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Glycogen Storage Disease Type II (Pompe Disease) [online] 1993 [viewed 26 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301438
  5. CONTI-FINE BM, MILANI M, KAMINSKI HJ. Myasthenia gravis: past, present, and future J Clin Invest [online] 2006 Nov 1, 116(11):2843-2854 [viewed 30 October 2014] Available from: doi:10.1172/JCI29894
  6. SPARKS S, QUIJANO-ROY S, HARPER A, RUTKOWSKI A, GORDON E, HOFFMAN EP, PEGORARO E, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Congenital Muscular Dystrophy Overview [online] 1993 [viewed 26 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301468
  7. PRIOR TW, RUSSMAN BS, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Spinal Muscular Atrophy [online] 1993 [viewed 26 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301526

Investigations - for Diagnosis

Fact Explanation
Full blood count Diagnosis is mainly based on history and clinical examination. Laboratory investigations are mainly focused on exclusion of other DD's and thereby supporting the diagnosis. FBC is one such essential investigation to be carried out.[1].
ESR and CRP Essential investigations,should be carried in all patients with suspected SMA to exclude other inflammatory causes.[1].
Creatine kinase level Affected individuals may have normal or increased creatine kinase level.[1],[2].
Electromyography (EMG) Denervation and diminished motor action potential amplitude is a recognized feature. An unique feature in SMA that can be identified in EMG is a regular spontaneous motor unit activity. Polyphasic waves, positive sharp waves, fibrillations as well as reduced interference pattern with maximal effort can be identified.[1],[3].
Nerve conduction velocities (NCV) Motor and sensory NCVs are usually found to be normal. Useful investigation to exclude other DD's[1].
Muscle biopsy Group atrophy of type 1 and type 2 muscle fibers can be identified. It is also useful to exclude certain other diseases mentioned under DD.[1].
Nerve histology In the prenatal forms of SMA there will be hypomyelination of the peripheral nerve. In other forms including distal SMA, nerves show normal histology.[1].
Molecular Genetic Testing The exact diagnosis of SMA is based on molecular genetic testing.Mutations in SMN1 gene can be identified. Presence of increased SMN2 copy numbers usualy modify the phenotype.[1].
References
  1. PRIOR TW, RUSSMAN BS, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Spinal Muscular Atrophy [online] 1993 [viewed 26 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301526
  2. YAMADA M, KANO M, CHIDA K, FURUKAWA T, TSUKAGOSHI H. Asymptomatic benign familial spinal muscular atrophy with hypertrophy of the calves and high creatine kinase levels. J Neurol Neurosurg Psychiatry [online] 1988 Mar, 51(3):452-453 [viewed 26 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1032885
  3. PRIDMORE C, BARAITSER M, BRETT EM, HARDING AE. Distal spinal muscular atrophy with vocal cord paralysis. J Med Genet [online] 1992 Mar, 29(3):197-199 [viewed 26 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1015897

Investigations - Fitness for Management

Fact Explanation
Random blood sugar Some affected individuals may at a risk of developing recurrent hypoglycemia. So to identify that this investigation is carried out.[1].
Lung function tests Not perform in all patients but only in suspected cases of respiratory involvement. FVC can be used for the assessment of lung functions by using hand-held spirometer.Decompensation during respiratory infection is more likely if FVC is less than 40%.[1]
Chest x ray Can perform suspected case of pneumonia which is a complication of encountered in SMA.[1]
References
  1. PRIOR TW, RUSSMAN BS, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Spinal Muscular Atrophy [online] 1993 [viewed 26 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301526

Investigations - Followup

Fact Explanation
Lung function test Carried out as a follow up investigation to assess FVC to assess risk of developing respiratory failure if their is any suspicion.[1].
References
  1. PRIOR TW, RUSSMAN BS, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Spinal Muscular Atrophy [online] 1993 [viewed 26 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301526

Investigations - Screening/Staging

Fact Explanation
Amniocentesis or chorionic villus sampling Performed in prenatal diagnosis in pregnancies.Analysis of DNA extracted from fetal cells is carried out Those DNA is extracted either by amniocentesis performed around ~15-18 weeks’ gestation or chorionic villus sampling performed around ~10-12 weeks’ gestation.[1].
References
  1. PRIOR TW, RUSSMAN BS, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Spinal Muscular Atrophy [online] 1993 [viewed 26 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301526

Management - General Measures

Fact Explanation
Proper counselling, patient and family education Once diagnosis is established proper counselling should be carried out by the doctor with the explanation of nature of the disease, life expectancy and complications. Educate them well regarding importance of proper follow up. Tell the family members that patient may not able do their day today works alone and they may need family members helping hand. Tell them that patient may need walking aids in the late stage of disease.[1].
Dietary measures There is no curative treatment for SMA. treatment is usually supportive. Dietary measures is need to prevent obesity in affected individuals in their adulthood.[1],[2].
Physiotherapy and occupational therapy Multidisciplinary approach is needed. Physiotherapy is carried out in order to prevent development of joint contractures and to improve functional outcomes.[1].
Respiratory support Not usually need in distal spinal muscular atrophy. Noninvasive respiratory support can be provided if there is a need.[1].
Orthosis Used to support the body and to aid walking. It allows the affected individual to be upright rather than prone but it does not prevent scoliosis. Orthosis may useful in late stage of disease.[1].
Pain killers Simple analgesics can be use if patient complains pain.[1].
Genetic Counseling It is "the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions." Since this is a autosomal recessive inherited disease genetic counselling is a must. Family members and patient should educate about the carrier detection methods as well as the family planing methods.[1].
References
  1. PRIOR TW, RUSSMAN BS, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Spinal Muscular Atrophy [online] 1993 [viewed 26 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301526
  2. D'AMICO A, MERCURI E, TIZIANO FD, BERTINI E. Spinal muscular atrophy Orphanet J Rare Dis [online] :71 [viewed 30 October 2014] Available from: doi:10.1186/1750-1172-6-71

Management - Specific Treatments

Fact Explanation
Orthopedic surgeries for scoliosis Need in some patients. If patients who are nonambulatory, develop spinal curvatures of more than 50 degrees, they may require a surgery. In case of severe scoliosis vertical expandable prosthetic titanium rib (VEPTR) can be used.[1].
Valproic acid (VPA) Drug treatment for SMA is still under investigation. VPA increases SMN protein levels through transcriptional activation. But it may also increases the expression of additional serine/arginine (SR). Drug causes few neurological side effects, hematological as well as hepatic side effect. Further studies by clinical trials is needed,[2],[1].
Phenylbutyrate It is a short-chain fatty acid. Studies suggest that it will stimulate SMN2 gene activity as well as increase SMN protein levels. It is less toxic and provides protection against various stimuli. However further studies is needed.[2],[1].
Gene therapy Still under experiment level.It is done by using viral vectors to replace SMN1.[3].
Stem cell therapy It also under the experiment level. Cell replacement is performed either by activation of endogenous stem cells in the CNS or transplantation of stem cell-derived cells that have undergone maturation in vitro.[3].
References
  1. PRIOR TW, RUSSMAN BS, PAGON RA, ADAM MP, ARDINGER HH, BIRD TD, DOLAN CR, FONG CT, SMITH RJH, STEPHENS K. Spinal Muscular Atrophy [online] 1993 [viewed 26 October 2014] Available from: http://www.ncbi.nlm.nih.gov/pubmed/20301526
  2. MOHSENI J, ZABIDI-HUSSIN ZA, SASONGKO TH. Histone deacetylase inhibitors as potential treatment for spinal muscular atrophy Genet Mol Biol [online] 2013 Sep, 36(3):299-307 [viewed 26 October 2014] Available from: doi:10.1590/S1415-47572013000300001
  3. D'AMICO A, MERCURI E, TIZIANO FD, BERTINI E. Spinal muscular atrophy Orphanet J Rare Dis [online] :71 [viewed 30 October 2014] Available from: doi:10.1186/1750-1172-6-71