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Methods Mol Biol 2018 ;1828:57-68

Department of Medical Genetics, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB, Canada.

Spinal muscular atrophy (SMA) is an autosomal recessive disorder caused by a mutation in SMN1 that stops production of SMN (survival of motor neuron) protein. Insufficient levels of SMN results in the loss of motor neurons, which causes muscle weakness, respiratory distress, and paralysis. A nearly identical gene (SMN2) contains a C-to-T transition which excludes exon 7 from 90% of the mature mRNA transcripts, leading to unstable proteins which are targeted for degradation. Read More

Handb Clin Neurol 2018 ;148:591-601

Neurogenetics Branch, National Institutes of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, United States. Electronic address:

Autosomal-recessive proximal spinal muscular atrophy (Werdnig-Hoffmann, Kugelberg-Welander) is caused by mutation of the SMN1 gene, and the clinical severity correlates with the number of copies of a nearly identical gene, SMN2. The SMN protein plays a critical role in spliceosome assembly and may have other cellular functions, such as mRNA transport. Cell culture and animal models have helped to define the disease mechanism and to identify targets for therapeutic intervention. Read More

Orphanet J Rare Dis 2017 04 11;12(1):67. Epub 2017 Apr 11.

Department of Neurology and Neurosurgery, F02.230, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, Heidelberglaan 100, 3508 GA, Utrecht, The Netherlands.

Background: Hereditary proximal spinal muscular atrophy (SMA) is a severe neuromuscular disease of childhood caused by homozygous loss of function of the survival motor neuron (SMN) 1 gene. The presence of a second, nearly identical SMN gene (SMN2) in the human genome ensures production of residual levels of the ubiquitously expressed SMN protein. Alpha-motor neurons in the ventral horns of the spinal cord are most vulnerable to reduced SMN concentrations but the development or function of other tissues may also be affected, and cardiovascular abnormalities have frequently been reported both in patients and SMA mouse models. Read More

Pediatr Clin North Am 2015 Jun 11;62(3):743-66. Epub 2015 Apr 11.

Division of Clinical Neurology, Department of Neurology, Boston Children's Hospital, 300 Longwood Avenue, Fegan 11, Boston, MA 02115, USA. Electronic address:

Spinal muscular atrophies (SMAs) are hereditary degenerative disorders of lower motor neurons associated with progressive muscle weakness and atrophy. Proximal 5q SMA is caused by decreased levels of the survival of motor neuron (SMN) protein and is the most common genetic cause of infant mortality. Its inheritance pattern is autosomal recessive, resulting from mutations involving the SMN1 gene on chromosome 5q13. Read More

Eur J Anaesthesiol 2015 Mar;32(3):211-3

From the Department of Anesthesiology, Academic Medical Center (KEH), Department of Surgery (BJD), Department of Internal Medicine (MS), Department of Anaesthesiology, Slotervaart Hospital (AJP), Amsterdam, The Netherlands.

Masui 2013 Jun;62(6):702-4

Department of Anesthesiology, Yao Municipal Hospital, Yao 581-0069.

We report a 61-year-old woman (weight 49 kg, height 156 cm) with Kugelberg-Welander disease who was scheduled for bilateral mastectomy under general anesthesia. We administered rocuronium 10 mg (0.20 mg x kg(-1)) for tracheal intubation. Read More

J Neurodegener Dis 2013 24;2013:903875. Epub 2013 Mar 24.

Service of Neurology CHU of Constantine, Algeria ; Laboratory of Biochemistry CHU of Constantine, Algeria.

Spinal muscular atrophy (SMA) is the second most common lethal autosomal recessive disorder. It is divided into the acute Werdnig-Hoffmann disease (type I), the intermediate form (type II), the Kugelberg-Welander disease (type III), and the adult form (type IV). The gene involved in all four forms of SMA, the so-called survival motor neuron (SMN) gene, is duplicated, with a telomeric (tel SMN or SMN1) and a centromeric copy (cent SMN or SMN2). Read More

J Anesth 2012 Apr 25;26(2):306-7. Epub 2011 Dec 25.

J Neurosurg Anesthesiol 2011 Apr;23(2):170-1

Rev Med Inst Mex Seguro Soc 2010 May-Jun;48(3):317-9

Instituto Mexicano del Seguro Social, Mexicali, Baja California, Mexico.

Spinal muscular atrophy (SMA) is an autonomic recessive disorder that affects the anterior horn cells of the spinal cord, degeneration of which results in proximal muscle weakness. It is classified into three types: I and II (Werdnig-Hoffmann disease) and III (Kugelberg-Welander disease). With an incidence of 1/10,000. Read More

Hum Mol Genet 2010 Nov 12;19(21):4239-52. Epub 2010 Aug 12.

Department of Pediatrics, The Research Institute at Nationwide Children's Hospital, Columbus, OH 43205, USA.

Proximal spinal muscular atrophy (SMA) is a neurodegenerative disease caused by low levels of the survival motor neuron (SMN) protein. In humans, SMN1 and SMN2 encode the SMN protein. In SMA patients, the SMN1 gene is lost and the remaining SMN2 gene only partially compensates. Read More

J Cardiovasc Electrophysiol 2009 Mar 13;20(3):342-4. Epub 2008 Oct 13.

Heart Rhythm Management Center, UZ Brussel, Vrije Universiteit Brussel, Brussels, Belgium.

We present a case of a 43-year-old male patient with adult onset of spinal muscular atrophy (SMA). The patient first came to our attention with atrioventricular (AV) block. A dual-chamber pacemaker (DDD-PM) was implanted. Read More

Rev Esp Anestesiol Reanim 2008 Aug-Sep;55(7):449-50

Neuropathology 2009 Feb 11;29(1):63-7. Epub 2008 Apr 11.

Department of Neurology, Suzuka National Hospital, Suzuka-shi, Mie, Japan.

We report an autopsy case of a 67-year-old man clinicogenetically diagnosed as having spinal muscular atrophy (SMA) type III (Kugelberg-Welander disease), showing slowly progressive muscle wasting and weakness of the extremities. His brother showed similar manifestations. Autopsy revealed neuronal loss and severe gliosis in the anterior horns of the spinal cord, a marked neurogenic change of skeletal muscles and mild degeneration of cardiomyocytes. Read More

Masui 2008 Mar;57(3):358-9

Department of Anesthesiology, Fukuoka University School of Medicine, Fukuoka 814-0180.

We report a 38-year-old man with Kugelberg-Welander disease who underwent triple arthrodesis for talipes equinovarus under combined spinal-epidural anesthesia supplemented with continuous intravenous infusion of propofol. There was no ventilatory disturbance, muscle weakness, or neurologic untoward event during perioperative period. Read More

Am J Med Sci 2006 Dec;332(6):354-6

Division of Cardiovascular Medicine, Department of Internal Medicine, Shimane University School of Medicine, Izumo City, Shimane, Japan.

There are few reports of cardiac involvement in patients with Kugelberg-Welander disease. We report a case of a 51-year-old man with Kugelberg-Welander disease who presented with syncope. His electrocardiogram showed complete right bundle branch block and transient complete atrioventricular block without escape rhythm. Read More

Neuromuscul Disord 2006 Aug 22;16(8):492-4. Epub 2006 Jun 22.

Department of Neurology, Children's Hospital Boston and Harvard Medical School, Fegan 11, 300 Longwood Avenue, Boston, MA 02115, USA.

Spinal muscular atrophy type III (SMA III, Kugelberg-Welander disease) typically presents with symmetric proximal weakness, areflexia, and hypotonia. We present four children with spinal muscular atrophy type III who had atypical phenotypes. Three patients clearly had asymmetric weakness at presentation and two had upper motor neuron signs in the lower extremities (one patient had both features). Read More

Neth J Med 2005 Jun;63(6):227-9

Department of Intensive Care, Alkmaar Medical Centre, Alkmaar, The Netherlands.

Moraxella catarrhalis rarely causes severe infections or bacteraemia in healthy subjects. In the literature only four cases of clinical sepsis with M. catarrhalis have been described, mostly in immunocompromised patients. Read More

Pediatr Med Chir 2004 Mar-Apr;26(2):139-41

Dipartimento di Pediatria,Azienda Gravina, Caltagirone (CT).

Spinal Muscular Atrophy (SMA) is an autosomal recessive disease characterized by diffuse proximal and distal weakness due to deletions of the survival motor neuron (SMN) gene localised on chromosome 5q13. Pathological studies show decreased numbers of motorneurons in spinal cord. SMA was initially sub-classified clinically into three types base on age at onset and clinical course. Read More

Can J Neurol Sci 2004 Nov;31(4):530-8

Intern Med 2004 Oct;43(10):951-4

Department of Internal Medicine, Suzuka National Hospital, 3-2-1 Kasado, Suzuka, Mie 513-8501.

A rare complication of possible secondary dilated cardiomyopathy to Kugelberg-Welander disease was described in a 53-year-old patient with this inherent motor neuron disease, whom we diagnosed after a genetic analysis of the defective survival motor neuron gene. An association of sleep disordered breathing of Cheyne-Stokes respiration was diagnosed, which was virtually eliminated with continuous positive airway pressure via nasal mask. Considering the paucity of therapeutic options in most degenerative neuromuscular disorders, ameliorations in not only sleep quality but also cardiac function with continuous positive airway pressure have clinical implications. Read More

Int J Obstet Anesth 2004 Jul;13(3):192-5

Department of Anaesthesia, Essex Rivers Healthcare Trust, Colchester General Hospital, Colchester, UK.

We describe the conduct of general anaesthesia for a patient with spinal muscular atrophy Type III (Kugelberg-Welander disease) undergoing elective caesarean section. Apart from a delayed return of skeletal muscle power following non-depolarising neuromuscular blockade the procedure was uneventful. We found no previously published reports of general anaesthesia for caesarean section in this condition in the English language literature. Read More

Anaesth Intensive Care 2003 Feb;31(1):92-4

Department of Anaesthesia, The Royal Women's Hospital, Melbourne, 132 Grattan Street, Carlton, Vic. 3053.

This report describes a 33-year-old primigravid woman with spinal muscular atrophy Type III (Kugelberg-Welander syndrome). Elective caesarean section was performed at 38 weeks gestation under spinal anaesthesia. The implications of spinal muscular atrophy for anaesthesia for caesarean section are described. Read More

Anaesthesia 2003 Jan;58(1):96

Przegl Lek 2001 ;58(11):989-91

Klinika Neurologii Dzieciecej Wydziału Lekarskiego Collegium Medicum Uniwersytetu Jagiellońskiego, ul. Wielicka 265, 30-663 Kraków.

Progress of diagnostic methods in recognition of spinal muscular atrophy (SMA), the most common degenerative disease of the nervous system in children has been observed in the last years. It has been proved, that all types of SMA, phenotypically variable Werdnig-Hoffman and Kugelberg-Welander diseases are results of homozygous absence of the telomeric copy of SMN gene located on the long arm of chromosome 5; this discovery was very important for mechanisms investigation. Based on the evolution of SMA diagnostic, the results of diagnostic in 18 children hospitalized in the Department of Pediatric Neurology Collegium Medicum of Jagiellonian University are presented. Read More

Leuk Lymphoma 2001 Jul;42(3):561-6

Division of Haematology and Medical Oncology, Peter MacCallum Cancer Institute, Melbourne, Victoria, Australia.

A case of nephrotic syndrome due to minimal change glomerulonephritis complicating Hodgkin's disease in a man with a longstanding neurological disorder is presented. Treatment with combination chemotherapy resulted in a rapid improvement in the nephrotic syndrome, and complete remission of the Hodgkin's disease. Disease relapse occurred less than 12 months later without recurrence of the nephrotic syndrome and was refractory to further treatment. Read More

Brain Pathol 2001 Apr;11(2):231-47

Department of Medical Physiology, University of Copenhagen, Denmark.

Spinal muscular atrophy (SMA) is a hereditary neurodegenerative disease caused by homozygous deletions or mutations in the SMN1 gene on Chr.5q13. SMA spans from severe Werdnig-Hoffmann disease (SMA 1) to relatively benign Kugelberg-Welander disease (SMA 3). Read More

Neurologia 2000 Nov;15(9):393-400

Servicio de Genética, Hospital de la Santa Creu i Sant Pau, Barcelona.

Spinal muscular atrophy (SMA) is an autosomal recessive neuromuscular disease characterized by degeneration and loss of motor neurons of the anterior horn of the spinal cord. The clinical manifestations include proximal symmetric weakness and progressive atrophy of muscle. SMA is classified by age of onset, severity of symptoms, and evolution in three groups: type I, severe or Werdnig-Hoffmann disease, type II or intermediate and type III, moderate-mild, Kugelberg-Welander disease. Read More

Ryoikibetsu Shokogun Shirizu 1999 (27 Pt 2):371-4

Department of Pediatrics, Tokyo Women's Medical University.

Neurol India 1997 Oct-Dec;45(4):271-272

Department of Neurology and Neurosurgery, Madurai Medical College and Govt. Rajiv Hospital, Madurai - 625 020, Tamilnadu, India.

Ehlers-Danlos Syndrome (EDS) is a group of heritable connective tissue disorders characterised by hyperelasticity of the skin and hypermobile joints. In addition to those features it is often associated with many systemic complications. Though many neurological complications have been described, an association of spinal muscular atrophy (SMA) has not been reported. Read More

Nat Genet 1997 Jul;16(3):265-9

Unité de Recherches sur les Handicaps Génétiques de L'Enfant, INSERM, Unité 393, IFREM, Institut Necker, Hôpital des Enfants Malades, Paris, France.

Spinal muscular atrophy (SMA) is a common autosomal recessive neuromuscular disorder characterized by degeneration of motor neurons of the spinal cord. Three different forms of childhood SMA have been recognized on the basis of age at onset and clinical course: Werdnig-Hoffmann disease (type-1), the intermediate form (type-II) and Kugelberg-Welander disease (type-III). A gene termed 'survival of motor neuron' (SMN) has been recognized as the disease-causing gene in SMA. Read More

Ann Neurol 1997 May;41(5):631-8

Department of Human Genetics, Sackler Faculty of Medicine, Tel Aviv University, Israel.

Progressive proximal muscle weakness is present both in spinal muscular atrophy (SMA) type III (Kugelberg-Welander disease) and in GM2 gangliosidosis, diseases that segregate in an autosomal recessive fashion. The SMN gene for SMA and the HEXA gene for GM2 gangliosidosis were investigated in a woman with progressive proximal muscle weakness, long believed to be SMA type III (Kugelberg-Welander type). She and her family underwent biochemical studies for GM2 gangliosidosis. Read More

Rev Neurol (Paris) 1997 Mar;153(2):120-3

Service de Neurologie, CHU Bicêtre, Le Kremlin-Bicêtre.

GM2 gangliosidosis are caused by a beta-hexosaminidase A enzyme deficiency. Mutations in the gene leaving residual enzyme activity give rise to juvenile and adult forms of the disease which have a great clinical heterogeneity. We report three cases which have been considered for some time as Kugelberg-Welander disease. Read More

Electromyogr Clin Neurophysiol 1996 Dec;36(8):469-75

Department of Neurology, University Hospital Tzaritza Ioanna, Sofia.

The term limb girdle syndrome includes a variety of neuromuscular disorders like the scapulohumeral and pelvifemoral types of muscular dystrophy, quadriceps myopathy and Wohlfart-Kugelberg-Welander syndrome. There may be considerable difficulty in distinguishing between different types of limb girdle syndrome, even with the aid of electromyographic and muscle biopsy examinations. The aim of this investigation was to reestablish the clues for distinguishing between different types of limb girdle syndrome. Read More

Arq Neuropsiquiatr 1996 Sep;54(3):402-6

Universidade Federal de São Paulo--Escola Paulista de Medicina (UNIFESP-EPM), Brasil.

We added hydrotherapy to 50 patients with spinal muscular atrophy (SMA) who were being treated with individual conventional physiotherapy. Hydrotherapy performed at an approximate temperature of 30 degrees Celsius, twice a week, for thirty minutes in children and forty-five minutes in adults during a 2-year period. The outcome derived from this combined modality of treatment was rated according to physiotherapeutic evaluations, the MMT (Manual Muscular Test), and the Barthel Ladder. Read More

Schweiz Med Wochenschr 1996 May;126(21):907-14

Institut für Medizinische Genetik, Universität Zürich.

Autosomal recessive spinal muscular atrophy (SMA) is, after cystic fibrosis, the second most common fatal monogenic disorder. The disease is characterized by degeneration of anterior horn cells leading to progressive paralysis with muscular atrophy. Depending on the clinical type (Werdnig-Hoffmann = type I, intermediate form = type II, Kugelberg-Welander = type III), SMA causes early death or increasing disability in childhood. Read More

Arch Mal Coeur Vaiss 1996 May;89(5):611-7

Service de cardiologie infantile, Hôpital Roger Salengro, CHRU de Lille.

Kugelberg-Welander disease is a juvenile form of slowly progressive spiral amyotrophy in which the incidence of cardiac involvement is difficult to appreciate as cases are sporadic. Classically, it presents with atrial hyperexcitability with variable degrees of atrioventricular block. In order to assess the prevalence of cardiac involvement in this condition, the authors undertook a prospective study in 8 patients with Kugelberg-Welander disease. Read More

J Med Genet 1996 Apr;33(4):281-3

Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U-393, IFREM, Institut Necker, Hôpital des Enfants-Malades, Paris, France.

Spinal muscular atrophy (SMA) is characterised by degeneration of anterior horn cells of the spinal cord and represents the second most common, lethal, autosomal recessive disorder after cystic fibrosis. Based on the criteria of the Internatinal SMA Consortium, childhood SMAs are classified into type I (Werdnig-Hoffmann disease), type II (intermediate form), and type III (Kugelberg-Welander disease). Recently, two genes have been found to be associated with SMA. Read More

Rev Esp Anestesiol Reanim 1995 Nov;42(9):402-3

Anaesthesia 1994 Aug;49(8):696-7

Department of Anaesthesia, Frenchay Hospital, Bristol.

A patient with Kugelberg-Welander disease presented as an unexpected difficult intubation. Tracheal intubation was achieved through the laryngeal mask airway, while regurgitation was prevented with continuous cricoid pressure. Regurgitation occurred after cricoid pressure was released. Read More

Pediatr Med Chir 1994 Mar-Apr;16(2):125-8

Cattedra di Neonatologia e Servizio Autonomo di Cardiologia Pediatrica, Università di Catania, Italia.

There are few cardiological studies in progressive spinal muscular atrophy and mainly concern subjects affected by the juvenile form (Kugelberg-Welander disease). The presence of a cardiomyopathy has been reported in these patients but the cardiac involvement is often secondary to the chronic respiratory insufficiency typical of the disease. We performed a retrospective study in our Institute on 43 patients, age range 3 months to 3 years, 37 of which presented type I (Werdnig-Hoffmann disease) and 6 type II (intermediate form) of the disease. Read More

Braz J Med Biol Res 1993 Nov;26(11):1157-73

Departamento de Bioquímica, Universidade de São Paulo, Brasil.

1. Five Brazilian families referred to us with a probable diagnosis of chronic proximal spinal muscular atrophy (Kugelberg-Welander) were identified, and permanent (Epstein Barr virus transformed) cell lines were established from members of four of the families. 2. Read More

Hum Hered 1993 Nov-Dec;43(6):380-7

Department of Psychiatry, Columbia University, College of Physicians and Surgeons, New York, NY 10032.

We have previously reported the mapping of the chronic (type II/intermediate and type III/mild/Kugelberg-Welander) form of the childhood-onset spinal muscular atrophies (SMA) to chromosome 5q11.2-13.3, with evidence for nonallelic genetic heterogeneity within a small sample of seven families [Brzustowicz et al. Read More

Am J Dis Child 1993 Jul;147(7):793-4

Department of Pathology and Laboratory Medicine, University of Wisconsin, Madison.

Acta Univ Palacki Olomuc Fac Med 1993 ;136:37-9

EMG Laboratory, Clinic of Neurology, Medical Faculty, Palacký University, Olomouc, Czech Republic.

Motor neuron disease (MND) and spinal muscular atrophies (SMA) are difficult to diagnose with classical EMG methods because significant findings appear relatively late and both groups of diseases show neurogenic type of record differing only in a relatively greater amount of fasciculations and higher amplitude of motor unit potential (MUP) in MND compared with SMA. We examined 12 patients with MND-amyotrophic lateral sclerosis and 7 patients with SMA type III and IV according to Swash with advanced EMG techniques-magnetic stimulation, single fiber and macro EMG. With transcranial magnetic stimulation, a significant prolongation of cortical latency was found in MND (P < 0. Read More

Neurol Neurochir Pol 1992 Sep-Oct;26(5):723-8

Kliniki Neurologicznej AM, Białymstoku.

The reported case was diagnosed in a girl aged 14, in whom the first signs developed at the age of 6, with progressive involvement of the cranial nerves IX, X, XI and XII, and V with VII. After ruling out other possible causes the diagnosis of the Fazio-Londe disease was established. Electromyographic examination confirming the diagnosis demonstrated also evidence of changes of neurogenic type in the muscles of upper extremities despite absence of demonstrable clinical abnormalities, which, as suggest the authors, may support the hypothesis of the similarity of the disease to other forms of spinal muscular atrophy, such as Werdnig-Hoffman and Kugelberg-Welander diseases. Read More

No To Shinkei 1992 Jun;44(6):547-52

Department of Neurology, National Minamikyusyu Hospital, Kagoshima, Japan.

The childhood form of the spinal muscular atrophy (SMA) is classically subdivided into three groups on the basis of a combination of age of onset, milestones of development and age of survival: acute Werdning-Hoffmann (type I), intermediate Werdnig-Hoffmann (type II) and Kugelberg-Welander disease (type III). Now we examined 7 cases of type I and 9 cases of type II on clinical and histochemical ground. Of the total of 16 cases, 5 cases had a family history of the disease. Read More

Arch Phys Med Rehabil 1991 Jul;72(8):587-91

Department of Physical Medicine and Rehabilitation, Mayo Clinic, Rochester, MN 55905.

The medical records of 31 patients (19 male and 12 female) with clinical and electrophysiologic features of Wohlfart-Kugelberg-Welander syndrome were reviewed. The reported age at onset ranged from less than one year to 46 years, and the age at diagnosis ranged from three to 66 years. Proximal muscle weakness, especially of the lower extremities, and muscular atrophy were the predominant clinical features. Read More

Clin Chem 1991 Jan;37(1):36-9

Clinical Research Center, Utano National Hospital, Kyoto, Japan.

We measured with a radioimmunoassay the concentrations of carbonic anhydrase III (CA-III, EC 4.2.1. Read More

Nature 1990 Apr;344(6268):767-8

Unité de Recherches sur les Handicaps Génétiques de l'Enfant, INSERM U-12, Hôpital des Enfants Malades, Paris, France.

Proximal spinal muscular atrophies represent the second most common fatal, autosomal recessive disorder after cystic fibrosis. The childhood form is classically subdivided into three groups: acute Werdnig-Hoffmann (type I), intermediate Werdnig-Hoffmann disease (type II) and Kugelberg-Welander disease (type III). These different clinical forms have previously been attributed to either genetic heterogeneity or variable expression of different mutations at the same locus. Read More