A natural history study of late onset spinal muscular atrophy types 3b and 4.
BACKGROUND
Spinal muscular atrophy (SMA) is caused by a homozygous deletion of the survival motor neuron (SMN)1 gene. The nearly identical SMN2 gene plays a disease modifying role. SMA is classified into four different subtypes based on age of onset and clinical course (SMA types 1-4). The natural history of early onset SMA types 1-3a has been studied extensively. Late onset SMA is rare and disease course has not been studied in detail.


OBJECTIVE
To perform a prospective study on the clinical course and the correlation with SMN2 copy numbers of late onset SMA.


METHODS
Patients fulfilling the diagnostic criteria for late onset SMA (types 3b and 4) were included in the study. At inclusion and follow-up, muscle strength, respiratory function, functional status and quality of life were assessed. SMN2 copy number was determined in all patients.


RESULTS
Twelve patients were identified and included. Six patients were siblings from one family, two patients were brothers from a second family and four patients were sporadic cases. All patients carried four copies of the SMN2 gene. Median age of disease onset was 22.2 years (10-37). Age of disease onset in patients from family one was lower as compared to the other patients. None of the outcome measures changed after a follow-up of 2.5 years. Five patients reported an increase in fatigue and muscle weakness. None of the patients showed symptoms of respiratory insufficiency.


CONCLUSIONS
This study indicates that late onset SMA is not characterized by disease progression and that alternative or surrogate disease markers are required for the design of future trials. This study confirms the finding that SMN2 copy number is a SMA disease course modifier.
Piepers
S
S
Dept. of Neurology, Rudolf Magnus Institute of Neuroscience, University Medical Center Utrecht, HP G 02.320, 85500, 3508, GA Utrecht, The Netherlands. s.piepers-2@umcutrecht.nl
van den Berg
L H
LH
Brugman
F
F
Scheffer
H
H
Ruiterkamp-Versteeg
M
M
van Engelen
B G
BG
Faber
C G
CG
de Visser
M
M
van der Pol
W-L
WL
Wokke
J H J
JH
D000293:Adolescent; D017668:Age of Onset; D002648:Child; D018450:Disease Progression; D005221:Fatigue / Q000453:epidemiology; D005260:Female; D005500:Follow-Up Studies; D018628:Gene Dosage; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D018908:Muscle Weakness / Q000453:epidemiology; D009134:Muscular Atrophy, Spinal / Q000145:classification / Q000453:epidemiology / Q000235:genetics*; D009426:Netherlands / Q000453:epidemiology; D011446:Prospective Studies; D011788:Quality of Life; D012131:Respiratory Insufficiency / Q000453:epidemiology; D055532:SMN Complex Proteins / Q000235:genetics*; D055533:Survival of Motor Neuron 1 Protein / Q000235:genetics; D055540:Survival of Motor Neuron 2 Protein; D013997:Time Factors
D055532:SMN Complex Proteins; C526471:SMN1 protein, human; C526477:SMN2 protein, human; D055533:Survival of Motor Neuron 1 Protein; D055540:Survival of Motor Neuron 2 Protein