Janina Borkowska

A collaborative study on the natural history of childhood and juvenile onset proximal spinal muscular atrophy (type II and III SMA): 569 patients

We analyzed clinical data of 569 patients in two combined series with childhood and juvenile proximal SMA. This cohort included only patients who had achieved the ability to sit unaided (type II and III SMA). The survival rate among 240 type II patients (who sat but never walked) was 98.5% at 5 years and 68.5% at 25 years. SMA III (n = 329) (those who walked and had symptoms before age 30 years) was subdivided into those with an onset before and after age 3 years (type IIIa, n = 195; SMA IIIb, n = 134). In patients with SMA III, life expectancy is not significantly less than a normal population. The probabilities of being able to walk at 10 years after onset was 70.3%, and at 40 years, 22.0% in SMA IIa. For SMA IIIb, 96.7% were walking 10 years after onset and 58.7% at 40 years. The subdivision of type III SMA was justified by the probability of being ambulatory depending on age at onset; the prognosis differed for those with onset before or after age 3 years. The data provide a reliable basis of the natural history of proximal SMA and support a classification system that is based primarily on age at onset and the achievement of motor milestones.

Localization of the gene for X‐linked spinal muscular atrophy

We used probes for DNA polymorphisms on the X chromosome to study genetic linkage in seven families with X-linked adult-onset spinal muscular atrophy. We found significant linkage to the marker DXYS1 on the proximal X chromosome long arm and loose linkage or nonlinkage to markers elsewhere. Our analysis localizes the gene defect for this form of anterior horn cell disease.

Analysis of creatine kinase activity in 504 patients with proximal spinal muscular atrophy types I-III from the point of view of progression and severity

Mild to moderately elevated creatine kinase (CK) activity is a frequent biochemical finding in proximal spinal muscular atrophy (SMA). In a collaborative study on all types of childhood and juvenile onset SMA, we analysed the CK activity of 504 SMA patients (138 type I, 127 type II, 144 type IIIa, and 95 type IIIb patients). Under the assumption of a lognormal distribution of CK activity as the most appropriate statistical model, CK levels were transformed into logarithms and compared by standard deviation scores = CK-SDS (log). CK activity was statistically different between early and later onset SMA: in SMA I and II, about one-third of patients showed CK-SDS (log) >2 SD, the analysis of the means did not show significant differences. In SMA III, CK-SDS (log) was significantly higher (p < 0.01) than in the two other groups, which was most pronounced in SMA IIIb. More than 90% of SMA IIIb patients showed CK-SDS (log) values >2 vs. 57% in SMA IIIa. As similar values were obtained for a subgroup of 100 patients in whom the diagnosis of autosomal recessive SMA was confirmed by a deletion of the telomeric copy of the survival motor neuron gene, our results can be considered representative for SMA I–III. There was no correlation between CK level and disease duration. The fact that patients were ambulatory or chair-bound had no influence on CK activity in type III SMA. There was no sex influence in SMA I, II and IIIa. The observed higher male values in the group SMA IIIb are most likely the result of a lack of female patients with onset after puberty.

International collaborative study of the spinal muscular atrophies. Part 1. Analysis of clinical and laboratory data.

There is considerable variation in age of onset, though in over three-quarters of cases onset is before 4 years of age. A febrile episode, often of viral origin, may be present at the time of onset and might possibly be of aetiological significance, perhaps by precipitating the disease in a genetically predisposed individual. Reduced fetal movements and floopiness at birth are present in about one third of those cases where the onset is in early childhood. It would seem that when the onset is before 4 years of age, and particularly if the child has never been able to sit without support, the prognosis is much worse than in cases where the onset is after the age of 4 years. The proximal limb muscles are predominantly affected and muscle tone is usually reduced but pseudohypertrophy is uncommon. Rarely are the cranial nerves affected. Muscle fasiculations are present in about half the cases. Almost 10% of cases appear to be mentally retarded. With regard to the EMG findings, spontaneous activity, reduced full effort pattern increased potential amplitude and duration and increased motor unit territory appear to be the most reliable diagnostic criteria. Routine histological evidence of neurogenic atrophy seems to be a more reliable diagnostic criterion than muscle histochemistry. However, this may be only reflect the way in which the data were selected, that is, from cases where a muscle biopsy showed evidence of neurogenic atrophy on routine histology. Finally the serum level of creatine kinase is rarely very high and in more than half the cases it is normal. The CSF chemistry is always normal.

The Predictive Value of Achieved Motor Milestones Assessed in 441 Patients with Infantile Spinal Muscular Atrophy Types II and III

Proximal spinal muscular atrophy (SMA) is classified into three main subtypes (I–III), defined by age at onset and achieved motor milestones. As age at onset can be very early in SMA II and III (IIIa, onset <3 years) and does not necessarily correlate with prognosis, the question arises whether the child can be correctly assigned to a specific SMA type at the time of presentation based on the assessment of motor function. Therefore we studied the motor milestones in 175 SMA type II and 266 SMA type III patients. In SMA II, 73% of the patients sat within the normal age range (up to 9 months), the remainder learned to do so at ages between 10 and 30 months. In SMA III, the walking milestone was passed with delay (given an upper normal limit of 18 months) in 10% of all and 16% of SMA IIIa patients (median age 13 months, range 9–53 months). There was a correlation between late sitting and walking in SMA III, since those who sat after 9 months were responsible for the majority of delayed walkers. The median age when becoming chairbound did not differ between early-onset SMA III patients who walked with delay and those who walked within the normal age range (10.2 versus 10.5 years). In conclusion, a significant proportion of patients with early-onset SMA classified as SMA II on the basis of achieved motor function turned out to be SMA III at later follow-up. It is important to reassess a child in the first 2–4 years, to determine whether walking can be achieved with or without aids, as children who start to walk late have a similar favourable outcome for ambulation compared to earlier walkers.

Unaffected patients with a homozygous absence of the SMN1 gene

In this report, we present three families in which we identified asymptomatic carriers of a homozygous absence of the SMN1 gene. In the first family, the bialleleic deletion was found in three of four siblings: two affected brothers (SMA type 3a and 3b) and a 25-years-old asymptomatic sister. All of them have four SMN2 copies. In the second family, four of six siblings are affected (three suffer from SMA2 and one from SMA3a), each with three SMN2 copies. The clinically asymptomatic 47-year-old father has the biallelic deletion and four SMN2 copies. In the third family, the biallelic SMN1 absence was found in a girl affected with SMA1 and in her healthy 53-years-old father who had five SMN2 copies. Our findings as well as those of other authors show that an increased number of SMN2 copies in healthy carriers of the biallelic SMN1 deletion is an important SMA phenotype modifier, but probably not the only one.

Population data on acute infantile and chronic childhood spinal muscular atrophy in Warsaw

SummaryThis study provides epidemiological data on acute infantile (ASMA) and chronic childhood spinal (CSMA) muscular atrophy in Warsaw for the period 1976–1985. All calculations are based on the assumption that ASMA and CSMA result from mutations at two different gene loci. The incidence of ASMA and CSMA was 1 in 19474 live births with a corresponding gene and carrier frequency of 714 × 10−5 and 1 in 70, respectively. The prevalance of CSMA for the year 1985 was 1.26 × 10−5. These figures are higher than in similar studies in other countries. This fact might be connected with the careful ascertainment in this study.

Genetic investigations on chronic forms of infantile and juvenile spinal muscular atrophy

SummaryA material of 247 cases selected from 260 cases of spinal muscular atrophy in the Warsaw Department of Neurology in 1960–1974 was analyzed. The size of sibships was established and calculations were made of the mean distribution of the age at onset, also according to sex, for the different clinical forms, genetical proportions by the method of siblings and of probands, and coefficient of sib-sib correlation for the material as a whole and separately for males, femals and male-female pairs.The analysis shows the course of the disease to differ between the sexes and to be mild in males more often than in females, as is particularly noticeable in the higher age groups. Cases of Kugelberg-Welanders disease are predominantly male. The hypothesis is advanced that a proportion of male patients have a sex-linked modifying gene of a fairly high frequency (possibly of the range of 1 in 5 males, and 1 in 25, in the homozygous state, in females).Although it would not disprove conclusively the nosological distinctness of different forms of infantile and juvenile spinal muscular atrophy, the existence of the modifying gene, if proved, would tend rather to add to the likelihood of their constituting a single recessive autosomal disease.ZusammenfassungDie vorliegenden 247 Fälle wurden aus insgesamt 260 Beobachtungen spinaler Muskelatrophie an der Neurologischen Klinik in Warschau in den Jahren 1960–1974 herausgegriffen. Die Größe der betroffenen Sippen wurde bestimmt, und es wurde errechnet, wie häufig der Befall, bezogen auf die verschiedenen klinischen Formen, getrennt nach Geschlechtern und Altersbeginn war. Dies wurde nach der Methode der Verwandten- und Probandenanalyse durchgeführt, und es wurde der Koeffizient der Realation von Sippe zu Sippe sowohl getrennt für Knaben, für Mädchen und für Knaben- und Mädchen-Paare bestimmt.Die Analyse ergab, daß der Verlauf der Erkrankung bei den Geschlechtern verschieden war und bei den männlichen Probanden gutartiger erschien, wobei dies besonders bei den älteren Gruppen deutlich war. Unter den Fällen von Kugelberg-Welanderscher Erkrankung überwiegen die männlichen Probanden. Es wird die Möglichkeit erwogen, daß ein Anteil der männlichen Patienten Träger eines geschlechtsgebundenen modifizierenden Gens von einer recht hohen Häufigkeit (einer unter 5 Männern und einer unter 25 Frauen im homozygoten Zustand) sind.Obwohl dies nicht endgültig gegen das Vorliegen von nosologisch unterschiedlichen Formen von infantiler und juveniler spinaler Muskelatrophie sprechen würde, würde doch das Vorliegen eines modifizierenden Gens — sofern dies bestätigt würde — eher dafür sprechen, daß diese scheinbar unterschiedlichen Formen doch eine einzige recessiv autosomale Erkrankung darstellen.

Chronic from of childhood spinal muscular atrophy: Are the problems of its genetics really solved?☆

The authors discuss the differences between the two large series of chronic childhood spinal muscular atrophies (SMA)--their own comprising 273 cases, and that of Pearn et al. comprising 141 cases. The main difference concerns the predominance of males in the clinically milder later-onset group in the present series. The data of Pearn et al. (1978a, b) are quite different. The reason for the discrepancies is apparently a different selection of material. The present material is highly selective in favour of chronic cases, and Kugelberg-Welander cases are well-represented, whereas the percentage of Kugelberg-Welander cases in the material of Pearn et al. was very small. Differences in selection also appear to be responsible for discordance in observations regarding influence of sex on the course of the disease. The present data seem to support the view that most of the cases revealing chronic forms of SMA (both mild and severe) are not distinct genetically. However, the possible existence of a distinct subgroup in which sex influence is strongly expressed is not excluded.

Incidence of spinal muscular atrophy in Poland--more frequent than predicted?

Background: The application of molecular methods has enhanced and enlarged the diagnostics of spinal muscular atrophy (SMA) and its carriership. It allows for reliable epidemiological studies which are of importance to demography and genetic counseling. Methods: This study sought to evaluate the incidence of SMA in Poland, on the basis of the prevalence of the SMN1 gene deletion carrier state in the general population, as well as an analysis of all cases of SMA diagnosed in the years 1998–2005. Results: The prevalence of the SMN1 gene deletion carrier state was estimated at 1 per 35 persons (17/600), yielding an incidence of SMA equal to 1 per 4,900. By contrast, the incidence of SMA based on the results of the meta-analysis was an estimated 1 per 7,127 in Warsaw and 1 per 9,320 persons across Poland, suggesting that some cases of SMA remain undiagnosed. SMA1 predominated among the diagnoses, accounting for 69% of all cases. Conclusion: A high prevalence of the SMN1 deletion carrier state in the general population indicates that SMA could be a more frequent disease than is predicted by the epidemiological data regarding diagnosed cases.