Intrafamilial variability in lysosomal storage diseases

Abstract

In most lysosomal storage diseases clinical variability is found and affects age-of-onset, severity, and the degree of neurological involvement. Very often the variability is due to the existence of different mutations leading to the same enzyme deficiency. In most of the families with more than one person affected, the clinical picture is very similar. Intrafamilial variation has been reported in the lysosomal storage diseases related or not related to genetic heterogeneity. In families in which different affected persons have the same genotype, as in X-linked disorders, or autosomal recessive diseases in which both parents of the affected sibs are carriers and healthy, the variability must be due to factors not related to the genotype. On the other hand, when different mutations are present in the same family, the variability may be related to the differences in the genotype of the affected persons. Knowledge of the possibility of intrafamilial variability and its genetic basis is essential in clinical and prenatal diagnosis of the lysosomal storage diseases.

Homozygotic intronic GAA mutation in three siblings with late-onset Pompe's disease

“…Although the onset of symptoms was similar among them, around their thirties, they presented different degree of respiratory compromise. Sibling phenotype discordance in late-onset PD has been described by others, where 10 years difference in age of onset between affected sibs or different clinical symptoms were detected, attesting a spectrum of clinical presentation even in a similar genetic background as in a single sibship 13,14 . Other non-genetic factors as lifestyle, nutrition, other genetic modifiers, and environmental factors might contribute to explain such clinical inter and intra-familiar variability.…”

Highlighting intrafamilial clinical heterogeneity in late-onset Pompe disease

“…Intrafamilial variability in Pompe disease, as well as in other glycogen storage diseases, has already been reported in the literature [4], [5]. It is probable that additional genes as well as non-genetic factors such as life-style, nutrition or still unknown environmental modifiers influence disease expression in siblings.…”

“…The late onset form of the disease has a variable age of onset and is characterized by a spectrum of symptoms and phenotypes that largely comprise a slowly progressive myopathy and respiratory muscle involvement [1], [2]. Intrafamilial phenotypic variability has been reported in Pompe disease, as well as in other glycogen storage diseases even in siblings sharing a similar genetic background [3], [4], [5].…”

The Role of Genetic Counseling in Pompe Disease After Patients Are Identified Through Newborn Screening

“…6 Phenotype discordance (ie, onset, course, and severity) has been observed within and between families with identical GAA genotypes of patients presenting with non-classic IOPD (patients presenting with symptoms before the age of 12 months but without cardiomyopathy) and patients with LOPD (patients with symptom onset after 12 months of age), 6 indicating that other factors (eg, environmental and epigenetic) may modify the clinical course in patients. [7][8][9] Children with classic IOPD have not historically survived to adulthood to reproduce, although the availability of enzyme replacement therapy (ERT) may improve their fitness and prolong their survival. All of the offspring of an individual with Pompe disease are obligate heterozygotes (carriers) for a pathogenic variant in GAA, although they may inherit different alleles.…”