Despite being well known as a cause of spinocerebellar symptoms and developmental delay in childhood, jGM2 is poorly studied with regard to the initial symptomatology and clinical course of the disease. We report here a comprehensive, combined retrospective and prospective study of 21 patients with the disease, supplemented by a review of another 134 patients previously reported as case reports or small series in the medical literature.
The definition of jGM2 is not always clear. The age of onset of earliest symptoms, rather than the age at diagnosis, is generally considered to distinguish patients with jGM2, and many would restrict the diagnosis to patients who show the onset of symptoms between 2 and 10 years of age.7
A careful review of the clinical history of many cases classified as adult onset or chronic GM2 gangliosidosis showed that symptoms actually began in childhood and adolescence.||
This misclassification of patients with jGM2 has the effect of biasing our understanding of the clinical course of the disease by excluding patients with early onset of symptoms but a relatively mild and slowly progressive course. For our study, we classified patients as having jGM2 when symptoms first appeared between 1 and 18 years of age, which would include, by convention, all patients in the pediatric age group.
Our patients, derived from 2 widely separated medical centers in Canada and Brazil, were from many different ethnic backgrounds. The increased number of patients of Brazilian Portuguese and Brazilian Jewish extraction is not surprising, considering that one of the centers is located in Brazil. The R178H mutation, which accounted for 5 mutant HEXA
alleles, was common in patients of Portuguese ancestry (patients 12–14 and 19). This is a common mutation associated with the B1 TSV and has been reported previously in patients of Portuguese ancestry.96,97
The observation that this mutation was particularly common among the Brazilian patients suggests a founder effect. The relatively small proportion of patients of Ashkenazi Jewish ancestry was somewhat surprising, considering the frequency of HEXA
mutations in members of this ethnic group. It is interesting to note that among the patients with the TSV, the most common mutation was the 1278insTACT, which is frequently found in Ashkenazi Jews2,4
; however, only 3 patients reported being Jewish. All patients reported with this mutation were compound heterozygous, with a second mutant allele associated with a juvenile-onset phenotype (patients 1, 2, 9, 10, 16, and 17).
This study showed that gait and speech disturbances, along with incoordination, were the most common symptoms at the onset of disease symptoms (). Behavioral or psychiatric symptoms, muscular weakness, intellectual impairment, and extrapyramidal signs were also frequently reported symptoms at disease onset (). In general, the age of onset and prevalence of different clinical features in our group of 21 patients were similar to those reported for the 134 patients reported previously. However, some differences were found, particularly an earlier age of onset for muscle wasting, proximal and distal weakness, and extrapyramidal signs among our own patients. In addition, diarrhea/constipation complaints, sleep problems, sphincter incontinence, poor weight gain, and acroparesthesia were more common in our series of patients (). To some extent, this may be explained by incompleteness of the published accounts of the cases reported in the literature. Our experience would suggest that these problems may be more common than previously thought. Failure to recognize their importance might result in inappropriate investigation and unnecessary delays in diagnosis.
This study showed few differences in the clinical phenotypes when comparing TSV and SV. Among the 21 studied patients, we observed that the age of onset of dysphagia, sleep problems, and sphincter incontinence was earlier in patients with the TSV. Among the cases previously reported in the literature, the age of onset for muscle wasting was earlier in the patients with the SV. The prevalences of diarrhea/constipation and sleep problems were higher in patients with the SV. However, all remaining clinical features analyzed in our studied group, along with the previously reported cases, showed no statistically significant differences between the SV and TSV subgroups ().
Analysis of the median of symptom latencies () provides a summary of the disease course. The gait disturbances were the earliest symptom, followed by speech problems, incoordination, intellectual impairment, seizures, extrapyramidal signs, incontinence of sphincters, and upper motor neuron signs. Dysphagia, along with diarrhea/constipation, tended to emerge later, with a median onset of 3 to 3.5 years. Behavioral or psychiatric problems, proximal and distal weakness, and muscle wasting also tended to appear late in the disease course.
Brain imaging studies showed that the most frequent finding in our studied patients and previously reported cases has been cerebellar atrophy, followed by generalized cerebral atrophy. It is interesting to note that the white matter changes and generalized cerebral atrophy seem to precede the appearance of cerebellar atrophy, which tends to be noted in the late teen years. Magnetic resonance spectroscopy has revealed low N
-acetylaspartate concentrations in basal ganglia as the disease progresses, which is consistent with a recent publication that reported findings on an older population of the same chronic subtype of GM2 gangliosidosis.101,102
The Kaplan-Meyer survival curve () based on the 21 studied patients and 30 previously reported deceased patients is the first published analysis of survival in patients affected with jGM2. The survival curve indicates that nearly half of the patients affected with the condition die in the first decade. It also shows that fully one quarter of patients live into the late teen years.
Results of the analysis of genotype-phenotype correlations were instructive and indicate that prediction of the disease course and longevity on the basis of age of onset alone may be inaccurate. The presence of some mutations, such as R178H in the HEXA gene, along with a mutation generally associated with the infantile TSV phenotype (c.1278insTATC or c.1073 + 1G→A) predicts an early onset and relatively rapid course of disease. Similarly, the R499H allele, again in combination with a severe HEXA mutation, is associated with early and faster disease progression. However, in the latter, gastrointestinal, incontinence of sphincters, and pyramidal signs were more prominent. In contrast, the presence of G269S or W474C mutations is apparently associated with milder and more slowly progressive disease. Patients with 1 of these 2 mutations along with a deleterious mutation in their HEXA genes showed more pronounced behavioral or psychiatric problems, proximal weakness, incoordination, and gastrointestinal problems.
One limitation of our study was the lack of more detailed information and data from previously reported cases in the literature. The majority of the publications were single case reports or retrospective cross-sectional studies of small series of cases; none of them report prospective clinical data obtained over a period of time. In the vast majority of these published reports, mutation information was lacking. Therefore, information about mutation identification was not included here. The number of patients with the SV makes generalizations on disease course or genotype-phenotype correlation more speculative. In terms of the neuroradiologic data, considerable interval variation in brain MRI/magnetic resonance spectroscopy occurred among the patients who underwent >1 imaging study.
Delineation of the natural history of jGM2 is an important requirement for the evaluation of new therapies currently in development for the treatment of the disease. The details of the natural history of the disease summarized here provide direction for the identification of useful clinical end points for emerging clinical trials of the treatment of jGM2. Our data also show that mutation analysis is potentially useful for predicting the clinical course of this debilitating inherited metabolic condition in individual patients.