Pergamon Neuromusc. Disord., Vol. 4. No. 5/6, pp. 52%528, 1994

Copyright © Elesevier Science Ltd Printed in Great Britain. All rights reserved

0960-8966/94 $%00 + .00

0960-8966(94)00041-7

L E T T E R T O T H E E D I T O R

T H E N A T U R A L H I S T O R Y O F S E V E R E S P I N A L M U S C U L A R

A T R O P H Y - - F U R T H E R E V I D E N C E F O R C L I N I C A L S U B T Y P E S

J A A K K O IGNATIUS

D e p a r t m e n t o f M e d i c a l Gene t i c s , T h e F i n n i s h F a m i l y F e d e r a t i o n Vt ies t r l i i t to , K a l e v a n k a t u 16, F I N - 0 0 1 0 0 He l s ink i , F i n l a n d

Childhood spinal muscular atrophy (SMA) is usually divided into three different subtypes using the age at onset, milestones achieved and survival as classification criteria [1-3]. There is some overlap between the different subtypes, but most authors agree that those with clinical onset at birth or shortly thereafter and with inability to sit unaided have the shortest lifes- pan [4-6]. This clinical subtype, often desig- nated as Type 1 or severe SMA (Werdnig- Hoffmann disease) also appears to be the most consistent within sibships [6-7]. There are, however, different opinions as to the prognosis in this clinical subgroup, one reason being different diagnostic criteria used in the previous studies [8]. Patient cohorts from different popu- lations but analysed using same clinical and diagnostic criteria are thus needed to clarify the natural history of childhood SMA.

We have seen the survival curves of Type 1 SMA of Thomas and Dubowitz [9] and analyzed our own cohort of Finnish patients along the same lines.

This cohort of Type 1 SMA patients was ascertained as a part of the whole-population study of childhood SMA in Finland [7]. The whole material, ascertained through several sources, consists of 131 childhood onset SMA patients. Of these, 71 children born 1960-1988 were classified as severe SMA having the onset before six months of age and who never achieved the ability to sit. They came from 47 sibships with one affected child in 33 families, 2 affected in 14, 3 affected in 2 and 4 affected in 1 family. All cases were diagnosed as having SMA on the basis of clinical examination, elec- trophysiology and/or muscle biopsy and ful- filled the diagnostic criteria set out by the

International SMA Consortium [2-3]. Com- plete clinical and diagnostic data including the age at death were available for all the patients.

The clinical course in terms of age at onset and age at death was analysed in a similar manner to the recent English study: we calcu- lated mean and median ages of death in the complete cohort (Table 1) and in five groups determined by age of onset (Table 2). The cumulative percentages of children who had died at any given time after onset were also analyzed both as a complete cohort (Fig. 1) and in the five groups determined by age of onset (Fig. 2).

Table 1. Clinical details of whole cohort

Natural history of severe S M A ( n = 71)

Onset Birth - 5 months Mean age at onset 1.5 months Median age at onset 1.5 months

Range of age at death 2 months - 10 yr Mean age of death 8.75 months* Median age of death 7 months*

*Two cases were excluded from the calculations: one boy with onset at 2.5 months and never able to sit was trachenstomized at 10 months and survived 8 yr with artificial respiration. Another boy had the onset around three months of age and never achieved sitting ability but survived until 10 yr of age.

Table 2. Clinical details: death related to age of onset

Age of onset Number of Age of death Maximum (months) patients (months) survival

(months) Mean Median

Birth 19 3.4 4 10 0-1 14 5.7 6.25 10 >1-2 18 6.0 7.5 12 >2-3 12 12 14.5 20* 4-6 8 14 17.5 30

*Excluding the same two patients as in Table 1.

527

528 J . I G N A T I U S

-~ 80

~ 60

~ 40

~ 20

0

Severe SMA: Cumulative percentage death by age 100

i , , i i ,

0 10 2'0 30 Age (months)

Fig. 1. Cumulative percentage mortality related to age.

~100

80

.~ 60

m ~ 2o

~ 0

Severe SMA: Cumulative % death by onset

1 2 months

2 - ~ h s

, , , , , ~

1'0 . . . . . 20 30 Age at death (months)

Fig. 2. Cumulative percentage mortality related to age of onset.

Compared with the results obtained by Thomas and Dubowitz [9], the survival curves are strikingly similar and the natural history appears almost identical in English and Finnish patients suffering from severe child- hood SMA. The Finnish material includes also patients diagnosed before the 1980s which may explain the slightly poorer prognosis observed in this cohort. Those with onset neonatally or before two months of age have a uniform prognosis in both studies. Thus these patients appear to form a separate subgroup. Instead, those with onset after two months but before six months of age have a more variable prognosis: in both cohorts there is one excep- tional patient with onset around three months of age but with prolonged survival. This obser- vation is of potential importance in forth- coming therapeutic trials which may be based on length of survival. Based on the Finnish material, the clinical picture of severe SMA with onset before two months of age appears to be very uniform even within sibships: when the child had clinical onset at birth or before two months of age, the diagnosis was evident before two months also in all subsequent affected sibs [7]. This observation may be

relevant for genetic counselling of the SMA families as well as for the efforts to character- ize the mutations responsible for childhood SMA.

Acknowledgements--I thank Mrs Taina Miikkulainen for the skilful drawing of the figures.

REFERENCES

1. Dubowitz V. .4 Colour Atlas of Muscle Disorders in Childhood London: Wolfe Medical Books, 1989.

2. Munsat T L. Workshop Report. International SMA Collaboration. Neuromusc Disord 1991; 1: 81.

3. Munsat T L, Davies K E. Meeting Report. International SMA Consortium. Neuromusc Disord 1992; 2: 423-428.

4. Byers R K, Banker B Q. Infantile muscular atrophy. Arch Neurol 1961; 5: 140-164.

5. Emery A E H. The nosology of the spinal muscular atrophies. J Med Genet 1971; 8: 481-495.

6. Pearn J, Wilson J. Acute Werdnig-Hoffmann disease. Acute infantile spinal muscular atrophy. Arch Dis Child 1973; 48: 425-430.

7. Ignatius J. Childhood spinal muscular atrophy in Finland A clinical, genetic and nosological study. Acta Univ Tamper 1992; 358.

8. Dubowitz V. Chaos in classification in spinal muscu- lar atrophy (editorial). Neuromusc Disord 1991; 1: 77-80.

9. Thomas N H, Dubowitz V. The natural history of severe spinal muscular atrophy. Neuromusc Disord 1994; 4: 497-502.