Abstract
We present the case of a floppy neonate with marked and generalized weakness, respiratory insufficiency and fetal akinesia deformation sequence. The infant showed multiple joint contractures, two bone fractures and needed mechanical ventilation from birth to death at 16 days of age. Electrophysiological assessment showed electrically unexcitable motor and sensory nerves. Muscle biopsy showed diffuse atrophy of type I and type II fibers. Necropsy confirmed the diagnosis of infantile spinal muscular atrophy (SMA) with severe loss of motor neurons in anterior horns and motor nuclei of brainstem. There were also neuronal loss, gliosis, chromatolysis, ballooned cells, empty cell beds and neuronophagia figures in other brainstem and brain nuclei. Genetic analysis of the patient revealed homozygous deletions of survival motor neuron gene 1 (SMN1) and a single copy of SMN2 in region 5q13. This case confirms that the loss of spinal motor neurons underlies the muscular atrophy in severe cases of 5q SMA. This case also shows that the presence of multiple joint contractures, bone fractures and respiratory insufficiency in SMA in the neonatal period does not necessarily exclude the occurrence of classical deletions in the SMA 5q13 region. Rather, these atypical clinical findings show the extreme severity and prenatal onset of the disease in these SMA cases, which may be related with the occurrence of a single copy of SMN2 gene. More reports of clinically, pathologically and genetically well-documented cases are essential to define the different types of this disease.
Similar content being viewed by others
References
Banker BQ (1986) Arthrogryposis multiplex congenita: spectrum of pathologic changes. Hum Pathol 17:656–672
Brahe C (2000) Copies of the survival motor neuron gene in spinal muscular atrophy: the more, the better. Neuromuscul Disord 10:274–275
Courtens W, Johansson AB, Dachy B, Avni F, Telerman-Toppet N, Scheffer H (2002) Infantile spinal muscular atrophy variant with congenital fractures in a female neonate: evidence for autosomal recessive inheritance. J Med Genet 39:74–77
Felderhoff-Mueser U, Grohmann K, Harder A, Stadelmann C, Zerres K, Bührer C, Obladen M (2002) Severe spinal muscular atrophy variant associated with congenital bone fractures. J Child Neurol 17:718–721
Greenberg F, Fenolio KR, Hejtmancik JF, Armstrong D, Willis JK, Shapira E, Huntington HW, Haun RL (1988) X-linked infantile spinal muscular atrophy. Am J Dis Child 142:217–219
Grohmann K, Schuelke M, Diers A, Hoffmann K, Lucke B, Adams C, Bertini E, Leonhardt-Horti H, Muntoni F, Ouvrier R, Pfeufer A, Rossi R, Van Maldergem L, Wilmshurst JM, Wienker TF, Sendtner M, Rudnik-Schöneborn S, Zerres K, Hubner C (2001) Mutations in the gene encoding immunoglobulin mu-binding protein 2 cause spinal muscular atrophy with respiratory distress type 1. Nat Genet 29:75–77
Kelly TE, Amoroso K, Ferre M, Blanco J, Allinson P, Prior TW (1999) Spinal muscular atrophy variant with congenital fractures. Am J Med Genet 87:65–68
Kobayashi H, Baumbach L, Matise T, Schiavi A, Greenberg F, Hoffman EP (1995) A gene for a severe lethal form of X-linked arthrogryposis (X-linked infantile spinal muscular atrophy) maps to human chromosome Xp11.3-q11.2. Hum Mol Genet 4:1213–1216
Korinthenberg R, Sauer M, Ketelsen UP, Hanemann CO, Stoll G, Graf M, Baborie A, Volk B, Wirth B, Rudnik-Schöneborn S, Zerres K (1997) Congenital axonal neuropathy caused by deletions in the spinal muscular atrophy region. Ann Neurol 42:364–368
Lefebvre S, Burglen L, Reboullet S, Clermont O, Burlet P, Viollet L, Benichou B, Cruaud C, Millasseau P, Zeviani M, Le Paslier P, Frézal J, Cohen D, Weissenbach J, Munich A, Melki J (1995) Identification and characterization of a spinal muscular atrophy-determining gene. Cell 80:155–165
Lefebvre S, Burlet P, Liu Q, Bertrandy S, Clermont O, Munich A, Dreyfuss G, Melki J (1997) Correlation between severity and SMN protein level in spinal muscular atrophy. Nat Genet 16:265–269
MacLeod MJ, Taylor JE, Lunt PW, Mathew CG, Robb SA (1999) Prenatal onset spinal muscular atrophy. Eur J Paediatr Neurol 3:65–72
Martin Y, Valero A, Castillo E del, Pascual SI, Hernandez-Chico C (2002) Genetic study of SMA patients without homozygous SMN1 deletions: identification of compound heterozygotes and characterisation of novel intragenic SMN1 mutations. Hum Genet 110:257–263
Rodriguez JI, Palacios J (1991) Pathogenetic mechanisms of fetal akinesia deformation sequence and oligohydramnios sequence. Am J Med Genet 40:284–289
Rodriguez JI, Palacios J, Ruiz A, Sanchez M, Alvarez I, Demiguel E (1992) Morphological changes in long bone development in fetal akinesia deformation sequence: an experimental study in curarized rat fetuses. Teratology 45:213–221
Van der Steege G, Grootscholten PM, Vlies P van der, Draaijers TG, Osinga J, Cobben JM, Scheffer H, Buys CH (1995) PCR-based DNA test to confirm clinical diagnosis of autosomal recessive spinal muscular atrophy. Lancet 345:985–986
Van Toorn R, Davies J, Wilmshurst JM (2002) Spinal muscular atrophy with congenital fractures: postmortem analysis. J Child Neurol 17:721–723
Volpe JJ (2001) Neuromuscular disorders: levels above the lower motor neuron to the neuromuscular junction. In: Volpe JJ (ed) Neurology of the newborn, 4th edn. Saunders, Philadelphia, pp 642–670
Zerres K, Rudnik-Schöneborn S (2003) 93rd ENMC international workshop: non-5q-spinal muscular atrophies (SMA)—clinical picture. Neuromuscul Disord 13:179–183
Acknowledgements
We thank Dr. C. Cavada (Morphology Department, School of Medicine, Universidad Autonoma de Madrid) for advice and Brenda Ashley for English language assistance.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
García-Cabezas, M.A., García-Alix, A., Martín, Y. et al. Neonatal spinal muscular atrophy with multiple contractures, bone fractures, respiratory insufficiency and 5q13 deletion. Acta Neuropathol 107, 475–478 (2004). https://doi.org/10.1007/s00401-004-0825-3
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00401-004-0825-3